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Adele sent social media into a frenzy when she posted a photo in honor of her birthday that also showcased the singers stunning weight loss. Now, Access Hollywood can exclusively confirm what the Rolling In The Deep singer has been eating to attain her slim figure!

A source tells Access Hollywood that that Adele has been working with trained nutritionist Dr. Dominique Fradin-Read and has been eating a diet based on the French chef Michele Guerard, who serves up slimming nuveau cuisine.

The chef became famous in the 1970s for pioneering low-calorie French cuisine, swapping the regions famously butter and oil-filled dishes with healthier, lighter ingredients. Guerard recommends a non-restrictive diet so long as you have a healthy balance of natural food intake.

I am not a guru wholl tell you what to eat and what not to eat, the chef told TIME in a 2017 interview. As long as food comes from nature herself, I dont see why you shouldnt eat it and just as a reminder, Dominos Pizza does not come from nature! I believe you can eat anything as long as you keep a balanced diet.

WATCH MORE: Adele Looks Unrecognizable Showing Off Svelte Figure In Little Black Dress

But that doesnt mean Adeles transformation happened overnight. The source also revealed that the singer lost weight over the course of two years, and not only was she motivated and disciplined in her approach to training but was sure to maintain a healthy and balanced diet.

Dr. Fradin-Read declined to comment.

Adeles former personal trainer Pete Geracimo just confirmed on Instagram that the singer has a healthy approach to weight loss. Geracimo also defended Adele against what he called fat-phobic accusations.

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As Adeles former London-based personal trainer, its disheartening to read negative commentary and fat-phobic accusations questioning the genuineness of her amazing weight loss. In my personal experience of working with her through many highs and lows, she always marched to the beat of her own drum on her own terms. She never undermined her God-given talent in any way. She let her incredible voice do the talking, or should I say singing! She never once pretended to be something that she wasnt. What you saw was what you got. And we all LOVED it! When Adele and I started our journey together, it was never about getting super skinny. It was about getting her healthy. Especially post pregnancy and post surgery. When 25 dropped and the tour announced, we had to get ready for a 13 month gruelling schedule. In that time, she warmed to training and made better food choices. As a result, she lost considerable weight and people took notice. Her body transformation was splashed across every media outlet. The attention it generated was mind-blowing. Since she moved to LA, its been well documented that she underwent some tough personal changes. Its only natural that with change comes a new sense of self and wanting to be your best possible version. She embraced better eating habits and committed to her fitness and is sweating! I could not be prouder or happier for her! This metamorphosis is not for album sales, publicity or to be a role model. She is doing it for herself and for Angelo. My hope is that people appreciate the hard work that Adele has done to improve herself for the benefit to her and her family only. She did not lose the weight to make others feel bad about themselves. This personal transformation has nothing to do with me or you. Its about Adele and how she wants to live her life. She has not changed from the Adele we grew up with and have loved. There is just a little less of her to go around. #adele #fabulous #strong #songbird #transformation #powerful #voice #love #rumorhasit #pt

A post shared by Pete Geracimo (@petegeracimo) on May 7, 2020 at 10:14am PDT

As Adeles former London-based personal trainer, its disheartening to read negative commentary and fat-phobic accusations questioning the genuineness of her amazing weight loss, he captioned a photo of what appears to be him and Adele relaxing in a pool.

In my personal experience of working with her through many highs and lows, she always marched to the beat of her own drum on her own terms. She never undermined her God-given talent in any way. She let her incredible voice do the talking, or should I say singing! She never once pretended to be something that she wasnt. What you saw was what you got. And we all LOVED it!

When Adele and I started our journey together, it was never about getting super skinny. It was about getting her healthy. Especially post pregnancy and post surgery. When 25 dropped and the tour announced, we had to get ready for a 13 month grueling (sic) schedule. In that time, she warmed to training and made better food choices. As a result, she lost considerable weight and people took notice. Her body transformation was splashed across every media outlet. The attention it generated was mind-blowing.

WATCH MORE: Adeles Former Trainer Shuts Down Fat-Phobic Accusations After Slimmed-Down Birthday Pic

The trainer also made an apparent reference to Adeles high-profile divorce, writing that wanting change is only natural.

Since she moved to LA, its been well documented that she underwent some tough personal changes. Its only natural that with change comes a new sense of self and wanting to be your best possible version. She embraced better eating habits and committed to her fitness and is sweating! I could not be prouder or happier for her! This metamorphosis is not for album sales, publicity or to be a role model. She is doing it for herself and for Angelo.

My hope is that people appreciate the hard work that Adele has done to improve herself for the benefit to her and her family only. She did not lose the weight to make others feel bad about themselves. This personal transformation has nothing to do with me or you. Its about Adele and how she wants to live her life. She has not changed from the Adele we grew up with and have loved. There is just a little less of her to go around.

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Adele Used This French Diet To Help Achieve Drastic Weight Loss (EXCLUSIVE) - Access

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Mariah Huq looks great in curve-clinging denim these days and if you ask her, that's no thanks to carbs. In a recent Instagram post, the Married to Medicine cast member twirled around wearing a tight jumpsuit that showed off her slim physique. And in the hashtags she added to her caption, the fashion plate made sure to give credit to the popular diet she's following.

In one hashtag, the producer wrote "TRIMMING down," and in another one she spelled out: "Keto." Mariah has opened up about her low-carb, high-fat lifestyle before. Back in March she shared an example of the types of meals she's having lately and revealed herhack for beating cravings.

"I'm trying to stay fit so I'll just take an egg with spicy Guacamole!" she wrote. "When I'm on a diet I always cook [my family] everything I like or want, b/c I get full just from smelling it while I cook!" She does have her cheat days, though just like her fellow Keto enthusiast Briana Culberson does.

Showing a fried fish sandwich with coleslaw in a May 6 Instagram share, Mariah wrote: "YES fried fish Samich! What ya'll know bout that? Don't come hating either talking about spaghetti goes with this! This is more than enough for my cheat day!" She added "no Keto today" in the hashtags.

But whatever she waseating or not eating on the day she took this photo, it's clear that Mariah was feeling and looking fantastic.

Back in December, Mariah revealed that she had shed 14 pounds in five weeks. "Chile the struggle is real!" she wrote back then. "I'm letting have at Christmas..probably gain ever pound back#FACT." Or, maybe not.

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Mariah Huq Shows Off Her Gorgeous Figure After "Trimming Down" on the Keto Diet - Bravo

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In 1958, aphysiologist from the University of Minnesota School of Public Health observed that incidents of coronary heart disease were more common in middle-aged Americans than their European counterparts living in Mediterranean countries.

Ancel Keys postulated that acorrelation existed between peoples risk for heart disease and their eating habits and lifestyle.

This observation led Keys to launch his seminal study, with participants from seven countries around the world the United States, Italy, Greece, Yugoslavia, the Netherlands, Japan and Finland to verify the hypothesis.

Consequent research showed alarge discrepancy in the incidence and mortality of heart disease among the monitored populations.

Participants from Italy and Greece, especially Crete, who had similar eating habits, had the lowest heart disease rates among other participants. The same was true for their Japanese counterparts, whose diet was also plant-based, but lacked the unsaturated fat that Mediterranean populations were receiving mainly from olive oil.

Participants from Finland and the United States, on the other hand, had the highest rates of heart disease due to their high intake of saturated animal fat, the research concluded.

The Seven Countries Study demonstrated that low rates of heart disease can occur both with alow and ahigh intake of fat, depending on its nature and the dietary habits of the participants.

This revelation led to the formal definition of the Mediterranean diet in 1980 after the first results of the study were published by Harvard University.

On the fortieth anniversary of the publications of these results, experts from various fields spoke with Olive Oil Times about the characteristics of the diet and its future.

Markos Klonizakis, aclinical physiologist at Sheffield Hallam University, in England, said one of the benefits of the Mediterranean diet is that there are many variations, making it adaptable across cultures.

My team tried to apply aMedDiet closer to the Greek type, containing fruits, vegetables, legumes, fish, olive oil and more, Klonizakis said. Our research has repeatedly shown that the MedDiet can act defensively, providing short-term and longer-term benefits, either on its own or in conjunction with mild exercise.

Recently, we found that aMediterranean-style eating pattern can quickly lessen the impact of Type 2diabetes on microvessels, but more time is needed to ease the impact of aging on people, he added.

Klonizakis argued that the eating preferences of people can be shaped by many factors and the current pandemic may be one of them.

Unhealthy food is easier to prepare. Maybe the coronavirus pandemic is achance for us to start eating better, he said. Of course, eating patterns are also amatter of trend, for example, the vegan regime has many adherents even though its benefits are not widely established, but nutritional tradition usually endures through time.

David Katz, adoctor from Yale University and the founder of the True Health Initiative agrees. He told Olive Oil Times that part of the reason the Mediterranean diet is able to endure and remain popular is due to its cultural importance. It is not just apassing fad.

It has been making and keeping people healthy for generations, he said.

Katz added that supplementing the MedDiet with extra virgin olive oil makes it more pleasurable and enhances its health benefits. Following ahealthy diet helps to improve the immune system.

You can make extra virgin olive oil part of adietary pattern to improve your health acutely and reduce your risk of severe coronavirus infection, he said.

Mary Yannakoulia, an associate professor of nutrition and eating behavior at Harokopio University of Athens, named some of the traits of the Mediterranean diet demonstrated by numerous scientific studies.

Many studies have shown that higher adherence to the MedDiet, leads to lower risk for coronary disease, cancer, dementia and Alzheimers, she told Olive Oil Times. In my opinion, the MedDiet is ahealthy dietary pattern that can be used in Greece to promote the citizens health, and even prevent various diseases, given the availability of the staple Mediterranean food and its direct connection with the tradition and the culture of our country.

In 2013, the MedDiet was named as aUNESCO Intangible Cultural Heritage of Humanity for both its health benefits and its cultural importance to the Mediterranean region.

In spite of all this, Yannakoulia remains skeptical about the long-term adherence of consumers in Greece to the MedDiet.

It is aquestion of how much we have moved away from the MedDiet, she said. No easy answer exists, considering that eating habits change over time, as do societies.

Basic elements of the MedDiet continue to exist in the dietary patterns of people in Greece, such as the everyday use of olive oil and the frequent consumption of fruits, veggies, legumes and grains, she added. On the other hand, many people in Greece nowadays have started to consume more meat and processed food.

However, on the other side of the Atlantic, Lizzy Freier believes the Mediterranean diet will continue to gain popularity with younger consumers. Freier works at Technomic, afoodservice research and consulting company in Chicago, and said that the diet is linked to many current healthy eating trends.

These health trends include the growth of vegetable-forward diets and afocus on unprocessed foodsboth of which are core attributes of Mediterranean fare, she told Olive Oil Times. Emphasizing health benefits of Mediterranean items especially appeal to younger consumers who are conscientious, are increasingly changing their diets to limit animal products and are looking to include more natural foods.

Freier cited some market research statistics to back up her observation and said that 42 percent of consumers have tried and liked Mediterranean cuisine. An additional 37 percent have not yet tried aMediterranean eating plan, but would like to do so.

As health and diets evolve and consumption of ethnic food continues to expand, the Mediterranean diet is poised to grow as apopular cuisine that appeals to diners with flavorful, healthy dishes, Freier said.

Brynn McDowell, an American dietician and blogger, agrees that the Mediterranean diet is likely to continue growing in popularity in the U.S. She said the flexibility of the diet plays abig part in making it an easy eating plan to follow.

There arent any strict rules, instead its based on aset of guidelines such as including more fruits, vegetables, whole grains, legumes, beans and nuts, she told Olive Oil Times. Emphasis is placed on what you should add to your diet for health. While some foods, such as red meat and sugary desserts and pastries, are recommended to be enjoyed in moderation, they arent forbidden. This makes the Mediterranean diet easily customizable to your lifestyle.

McDowell sees this flexibility as away to prevent consumers from getting frustrated by the limitations of the diet, which is one of the key reasons why people find more strict diets harder to follow.

I feel like people are starting to get frustrated with the newest fad or restrictive diet and instead, getting back to falling in love with good food and healthy, fresh ingredients again, which is what the Mediterranean diet is all about, she said. Its my opinion that the Mediterranean diet is here and popular for the long haul.

The Mediterranean diet has been selected as the best diet of 2020 by the U.S. News and World Report. It was the third consecutive year that the eating plan was selected as the top diet.

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40 Years of the Mediterranean Diet: Whats Next for the Worlds Healthiest Eating Plan - Olive Oil Times

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My physicians support my low-carb lifestyle and, honestly, they are impressed with my tight control in less than a year out from my diagnosis, Alli tells Yahoo Life. (Photo courtesy of LowCarbDiabetic)

Receiving a diagnosis of diabetes can be shocking under ordinary circumstances. For Alli, the woman behind the popular Instagram account LowCarbDiabetic, the prognosis came right before she started medical school.

Im a career changer, and had some routine lab work done before leaving for medical school, Alli, tells Yahoo Life. My lab results showed dangerously high glucose levels. Glucose, aka sugar, is your bodys main source of energy, MedlinePlus explains. High glucose levels can be a sign of diabetes.

My doctor and I thought it might be an error because Ive been a runner and health nut for years, Alli says. But, after she did another glucose test, the diagnosis was official: She had diabetes.

It was a shocking diagnosis, but [it] made sense looking back at how Id been feeling over the last year, says Alli. She originally thought the fatigue she experienced and the fact that she was running slower than usual were due to school burnout. Alli also didnt pay a lot of attention to classic signs of diabetes, like having an increased appetite without gaining weight and being thirstier than usual.

Having diabetes is not for the faint-hearted, Alli says. If youre going to have good control, you have to find your inner warrior, she adds.

Alli now takes between four to six insulin injections a day and is very strict with her diet. She was already on a fairly low-carb diet at the time of her diagnosis, and shes maintained that.

But Alli admits she was confused when her doctor handed her a pamphlet from the American Diabetes Association (ADA) after her diagnosis that recommended she eat carbohydrates. It called for eating more carbs than I had in years.

Alli still gets carbs from fruits and vegetables, but shes cut out things like bread, rice, pasta and potatoes. Along with running regularly, she says that sticking to a low-carb diet has helped her reduce her insulin doses and helps keep her glucose levels within her target range.

Currently the ADA, notes on its website that eating too many carbs can raise your blood glucose too high. However, the organization adds, Eating too little carbohydrates can also be harmful because your blood glucose may drop too low, especially if you take medicines to help manage your blood sugar.

The ADA specifically recommends that patients with diabetes get their carbohydrates the most from whole, unprocessed, non-starchy vegetables like broccoli, tomatoes and green beans, and less from refined, highly-processed carbohydrate foods and foods with added sugar, like soda, white bread and cake. The ADA advises that minimally-processed carbs like brown rice, whole wheat bread, whole grain pasta and oatmeal are also OK.

While a low-carb diet may work for some patients with diabetes, its hard to say that its the right fit for all diabetic patients, according to Katherine Araque, MD, an endocrinologist and director of endocrinology of the Pacific Neuroscience Institute at Providence Saint Johns Health Center in Santa Monica, Calif. Its not one size fits all, says Araque.

Leigh Tracy, RD, a dietitian and diabetes educator at The Center for Endocrinology at Mercy Medical Center in Baltimore, agrees, telling Yahoo Life, that diabetics dont need to swear off carbs if they dont want to. Carbohydrates are not bad. They actually give your body necessary energy, she explains.

My physicians support my low-carb lifestyle and, honestly, they are impressed with my tight control in less than a year out from my diagnosis, she says.

After sharing her low-carb recipes with friends and family, Alli eventually decided to create an ebook of her recipes, called Beginners Guide for Low Carb Recipes.Its a lifestyle.

Despite her controlled diabetes, Alli says her condition is always on my mind. I just have to deal with it, she says. There are people with much more severe illnesses. I got a bad deal, but its really not that bad at the end of the day. Ive taken as much control as I can.

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The controversial diet that helped one woman control her diabetes - Yahoo Lifestyle

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I eat pancakes for breakfast every morning now. This is not because of quarantine (I started doing it well before the pandemic hit). This is not because I suffer from crippling depression and have given up on life. This is not because I am some elderly man whose eating habits never evolved past 1940. I am a healthy, vital and happy man who made the conscious decision to eat a stack of flapjacks at o'dark thirty every morning as part of a healthy, vital and happy routine. Pancakes complete me.

This might strike you as counterintuitive. After all, I'm 43 years old and I've already gone through the nutritional cycle of eating like a teen (garbage), eating like a twentysomething (takeout), eating like a thirtysomething (slightly more expensive takeout), and then finally coming to a rest in the California Zone, where I eat avocado toast without irony, dabble in the occasional farro salad, and even look FORWARD to having certain vegetables with dinner.Pancakes have no place in the California Zone. When I was 25, they were the perfect s---faced-at-a-diner-at-3 a.m. food. Two decades later, I feared them as if they were a tangible and very fluffy COVID-19 spore. Ask any licensed dietician what NOT to eat every day and they will show you a mugshot of an IHOP short stack. Pancakes consist of multiple layers of starch, all fried in fat, and then topped with a generous layer of pure maple sugar and a f---ing ice cream scoop of whipped butter. It's a ticking carb bomb. If you offer Jessica Alba pancakes for breakfast, she files a lawsuit.

So I feared pancakes. In 1996, I tipped the scales at a forbidding 280 lbs. I lost 80 of those pounds, but then slowly ascended back up to 260 lbs. by the time 2010 had rolled around. Again I dropped back down to 200 lbs. and have remained just a touch north of that ever since. To keep that weight off for good, I made a pact with myself to practice the dreaded PORTION CONTROL. No overloaded plates, no seconds, etc. Hence, every morning I used to eat breakfast like a coward. I would have a small bowl of cereal with an even smaller spoon. Or I would eat eggs. On their own. No toast. Or I would eat a small bowl of almond butter with honey and sea salt mixed in. That was a treat to me. Pathetic.

I have three kids, and all of them possess superhuman child metabolism. They can eat what they want, and eat any amount of it. They don't give a crap. I used to make them pancakes for breakfast every weekend, because that's a strong mob boss move. And every once in a while, I would treat myself to a single pancake, without any syrup on it. Afterward, I would experience the kind of food guilt that designated weight strugglers know with a terrifying intimacy. Can't believe I ate a whole pancake. Boy, the scale's not gonna be happy with me about this, buddyboy! I was firmly convinced the old adage of eating like a king for breakfast, like a prince for lunch, and like a pauper for dinner was a load of s---.

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Drew Magary: I'm on a pancake-only breakfast diet and I wish I started this sooner - SF Gate

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New US research has found that older adults who include plenty of flavonoid-rich foods in their diet, such as berries, apples and tea, may have a lower risk of developing Alzheimer's disease.

Carried out by researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University in Massachusetts, the new study looked at 2,801 participants aged 50 and older to investigate the relationship between eating foods containing flavonoids and the risk of developing Alzheimer's disease and other related dementias over a period of nearly 20 years.

Flavonoids are natural substances found in plants, fruits, and vegetables, such as pears, apples, berries, onions, and plant-based drinks like tea and wine, as well as in dark chocolate. They have previously been linked to a wide variety of health benefits, however previous studies which have looked at the link between nutrition and dementia have usually only looked at diet over a short period of time.

The findings of the new long-term study, published in the American Journal of Clinical Nutrition, showed that participants who had a low intake of three types of flavonoids appeared to have a higher risk of dementia than those with the highest intake.

More specifically, those with a low intake of flavonolds (found in apples, pears and tea) or a low intake of flavonoid polymers (in apples, pears and tea) appeared to have twice the risk of developing Alzheimer's disease and related dementias, while a low intake of anthocyanins (found in blueberries, strawberries and red wine) was associated with a four-fold risk of developing Alzheimer's disease and related dementias.

The researchers explain that a low intake was equal to no berries per month, around one-and-a-half apples per month and no tea. A high intake was equal to around 7.5 cups of blueberries or strawberries per month, eight apples and pears per month, and 19 cups of tea per month.

"Our study gives us a picture of how diet over time might be related to a person's cognitive decline, as we were able to look at flavonoid intake over many years prior to participants' dementia diagnoses," said senior author Paul Jacques. "With no effective drugs currently available for the treatment of Alzheimer's disease, preventing disease through a healthy diet is an important consideration."

"Tea, specifically green tea, and berries are good sources of flavonoids," said first author Esra Shishtar. "When we look at the study results, we see that the people who may benefit the most from consuming more flavonoids are people at the lowest levels of intake, and it doesn't take much to improve levels. A cup of tea a day or some berries two or three times a week would be adequate," she said.

Jacques also added that even later in life at age 50, which was the age at which the participants' first had their diets analyzed, it's still not too late to make positive diet changes. "The risk of dementia really starts to increase over age 70, and the take-home message is, when you are approaching 50 or just beyond, you should start thinking about a healthier diet if you haven't already," he said.

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Including more berries, apples and tea in the diet could protect against Alzheimer's - Yahoo News

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Health experts, as well as the media, have made it known that social distancing, wearing face masks and frequent hand-washing are the most effective ways to prevent transmission of the disease to others and minimize our own exposure to the virus. But we dont hear much, if anything, about other proactive steps we can take to decrease our risk of the disease and its complications.

The SARS-CoV-2 is a brand-new virus, so there are not many studies specific to it, but medical research is full of studies regarding lifestyle factors and their influence on the immune system and other infections, such as influenza.

The most influential lifestyle factor on our immune system is our diet. Everything we eat and drink affects our immune system, either positively or negatively. If you research scientific studies, you will find many foods, nutrients and supplements that have been analyzed regarding the immune system. Lets focus on five main groups of food/drink that have special immune-boosting benefits: fiber, alliums, cruciferous vegetables, tea and salads/spices.

Fiber in our diets which is only found in whole-plant foods, with the highest amounts in legumes and whole grains feeds the bacteria in our intestines, the gastrointestinal microbiome. These bacteria play a crucial role in our immune system function, helping form a barrier between the GI and respiratory tract and the bloodstream, and training and modulating our immune system through chemicals secreted, such as redox molecules and short-chain fatty acids. Studies show as much as 80% of our immune system lines our GI tract, with the microbiome directly influencing it.

Alliums are the garlic and onion family. They contain many beneficial ingredients that support our immune system, including fiber and allicin, a phytonutrient that has direct antiviral and immune-boosting properties.

Cruciferous vegetables like kale, cabbage, broccoli, cauliflower, radishes and asparagus also contain fiber, but are more known for their high level of sulfur-containing compounds that help our immune system fight infections.

Tea, especially green tea, is high in immune-boosting antioxidants and phytonutrients, such as catechins, which have been proven to help lower rates of viral infections like influenza and lessen the severity of symptoms if contracted.

Salads and spices are also well-known in the scientific literature to help boost our immune systems and help prevent and fight viral infections. Dark leafy greens, such as kale, swiss chard and spinach, are especially high in immune-enhancing antioxidants and help our bodies produce nitrous oxide, a strong antioxidant and potent dilator of blood vessels, improving blood flow to our organs. Spices, notably bay leaves, rosemary, turmeric and ginger, have been found in studies to be effective in preventing and fighting viral and respiratory infections and modulating inflammatory reactions. Berries and other brightly colored produce are also very high in antioxidants.

So be avid with hand-washing and mask-wearing, and smart with your social interactions, but also take advantage of this challenge to become a healthier eater. Enjoy oatmeal with berries and pumpkin pie spice and a cup of green tea for breakfast; vegetable bean soup with plenty of spices, onions and garlic and a side spinach salad for lunch; and maybe a lentil curry bowl with onions, ginger and curry spices over brown rice and kale for dinner, all loaded with immune-boosting fiber, antioxidants and phytonutrients!

Dr. Jason Buffington practices lifestyle medicine at Essentia Health.

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Healthier, happier: Diet is one way to decrease risk of coronavirus - Duluth News Tribune

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NEW YORK As the pet food and treat industry evolves to provide consumers with high-quality nutrition, convenience and individualization, Smalls has pounced at the opportunity to offer customized, human-grade, direct-to-consumer diets for cats.

According to Nielsen Pet Retail data for the 52 weeks ending June 2019, traditional wet pet foods are losing ground to fresh, refrigerated and frozen diets. Frozen wet pet food sales increased 8.8%, while refrigerated pet food sales grew 21.5%. Smalls cat food is operating on all fronts, offering custom diets in a variety of formats, including fresh and frozen options.

The company was founded by Calvin Bohn and Matt Michaelson in 2017 when direct-to-consumer diets for dogs such as Freshpet, JustFoodForDogs and Pet Plate were already taking the market by storm. Smalls was created to provide the same kinds of offerings for cat owners using an online quiz to recommend premium diet plans.

Smalls' co-founders, from left: Calvin Bohn, chief operating officer, and Matt Michaelson, chief executive officer.Each cat has unique needs, so all Smalls customers take a quiz to determine which formulas or recipes are best for their cats, Bohn explained. The quiz takes into account a cats age and weight, as well as what conventional foods theyve had in the past or are the most familiar with. This helps us make a recommendation on what the cat should have when it comes to Smalls.

From the quiz, the company suggests several options, some including a combination of formats including human-grade fresh diets (which are gently processed and flash-frozen for shipping), freeze-dried raw and kibble. Fresh options are available in minced and smooth pt formats. Smalls kibble options are formulated with a meat-first philosophy to provide high-protein nutrition.

Suggested products are then combined as part of a meal plan to offer variety. This could include a plan in which the base diet is dry kibble and a fresh meal-topper is provided. Other options include 50% dry and 50% fresh, a kibble and freeze-dried raw base with a fresh topper, kibble-only, all-fresh, and essentially every other possible combination of formats.

Cats are neophiles they crave newness and change, and most cat parents would be surprised to learn that includes what goes in a cats bowl, Bohn said.

Cat owners can also choose their proteins. Current options include chicken, turkey, beef, fish and duck, in either minced or pt formats. Smalls top-selling recipe is fresh minced chicken, the companys original formula. The company is currently developing new formulas to add to its cat food portfolio.

The diets are formulated by different nutritionists for different products, then vetted through our community of experts to validate the formulation, Bohn explained. Once we have a set formula, we manufacture test batches and run palatability studies (to make sure cats like the food) and test it in a lab to make sure the diet is complete and balanced with all essential vitamins and minerals.

For particularly picky eaters or cats having trouble transitioning from one food to another, Smalls provides a sample pack of diets and toppers, as well as customer support to assist cat owners, Bohn said.

Smalls doesnt offer specific formulas for things like food insensitivity or allergies, but our main product has had a lot of success in cats suffering from obesity, allergies and other diet-related issues, Bohn said. Its useful to think about it as transitioning from fast food (mass-market kibble and cans) to salads and a better-rounded diet: a whole bevy of health issues that you werent even necessarily aware were tied to your diet all of a sudden get resolved.

For its fresh/frozen diets, Smalls recommends thawing in the fridge for 24 hours before serving. The company provides a special container for pet owners to keep thawed leftovers and open packages fresh in the fridge between servings. Its freeze-dried, wet and kibble products are shelf stable.

Smalls also sells cat treats on its website, including chicken giblets, which are freeze-dried bits of chicken heart and liver, as well as bonito flakes, chicken broth and chicken liver powder to be served as meal toppers or to assist with food transitioning.

The company partners with a co-manufacturer based near Chicago to produce its cat food and treat products. The facility is human-grade and USDA-certified.

The company distributes within the continental United States. All complete-and-balanced diets are formulated to nutritional standards for cats of all life stages set by the Association of American Feed Control Officials (AAFCO).

Visit the cat food company's website for more information about Smalls.

Read more about pet food manufacturers.

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Customized nutrition isn't just for the dogs - Pet Food Processing

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Abstract

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

Osteoarthritis (OA) is a multifactorial family of diseases, characterized by cartilage degeneration, joint inflammation, and bone remodeling. Despite the broad impact of this condition, there are currently no disease-modifying drugs available for OA. Previous studies demonstrate that obesity and dietary fatty acids (FAs) play a critical role in the development of OA, and metabolic dysfunction secondary to obesity is likely to be a primary risk factor for OA (1), particularly following joint injury (2, 3). Furthermore, both obesity and OA are associated with a rapid loss of muscle integrity and strength (4), which may contribute directly and indirectly to the onset and progression of OA (5). However, the mechanisms linking obesity, muscle, and OA are not fully understood and appear to involve interactions among biomechanical, inflammatory, and metabolic factors (6). Therefore, strategies that focus on protecting muscle and mitigating metabolic inflammation may provide an attractive target for OA therapies in this context.

A few potential interventions, such as weight loss and exercise, have been proposed to reverse the metabolic dysfunction associated with obesity by improving the quantity or quality of skeletal muscle (7). Skeletal muscle mass is modulated by myostatin, a member of the transforming growth factor (TGF-) superfamily and a potent negative regulator of muscle growth (8), and myostatin is up-regulated in obesity and down-regulated by exercise (9). While exercise and weight loss are the first line of therapy for obesity and OA, several studies have shown difficulty in achieving long-term maintenance of weight loss or strength gain, particularly in frail or aging populations (10). Thus, targeted pharmacologic or genetic inhibition of muscle-regulatory molecules such as myostatin provides a promising approach to improving muscle metabolic health by increasing glucose tolerance and enhancing muscle mass in rodents and humans (8).

Follistatin (FST), a myostatin- and activin-binding protein, has been used as a therapy for several degenerative muscle diseases (11, 12), and loss of FST is associated with reduced muscle mass and prenatal death (13). In the context of OA, we hypothesize that FST delivery using a gene therapy approach has multifactorial therapeutic potential through its influence on muscle growth via inhibition of myostatin activity (14) as well as other members of the TGF- family. Moreover, FST has been reported to reduce the infiltration of inflammatory cells in the synovial membrane (15) and affect bone development (16), and pretreatment with FST has been shown to reduce the severity of carrageenan-induced arthritis (15). However, the potential for FST as an OA therapy has not been investigated, especially in exacerbating pathological conditions such as obesity. We hypothesized that overexpression of FST using a gene therapy approach will increase muscle mass and mitigate obesity-associated metabolic inflammation, as well as the progression of OA, in high-fat diet (HFD)induced obese mice. Mice fed an HFD were treated with a single dose of adeno-associated virus 9 (AAV9) to deliver FST or a green fluorescent protein (GFP) control, and the effects on systemic metabolic inflammation and post-traumatic OA were studied (fig. S1).

Dual-energy x-ray absorptiometry (DXA) imaging of mice at 26 weeks of age (Fig. 1A) showed significant effects of FST treatment on body composition. Control-diet, FST-treated mice (i.e., Control-FST mice) exhibited significantly lower body fat percentages, but were significantly heavier than mice treated with a GFP control vector (Control-GFP mice) (Fig. 1B), indicating that increased muscle mass rather than fat was developed with FST. With an HFD, control mice (HFD-GFP mice) showed significant increases in weight and body fat percentage that were ameliorated by FST overexpression (HFD-FST mice).

(A) DXA images of mice at 26 weeks of age. (B) DXA measurements of body fat percentage and bone mineral density (BMD; 26 weeks) and body weight measurements over time. (C) Serum levels for adipokines (insulin, leptin, resistin, and C-peptide) at 28 weeks. (D) Metabolite levels for glucose, triglycerides, cholesterol, and FFAs at 28 weeks. (E) Serum levels for cytokines (IL-1, IL-1, MCP-1, and VEGF) at 28 weeks. (F) Fluorescence microscopy images of visceral adipose tissue with CD11b:Alexa Fluor 488 (green), CD11c:phycoerythrin (PE) (red), and 4,6-diamidino-2-phenylindole (DAPI; blue). Scale bars, 100 m. Data are presented as mean SEM; n = 8 to 10; two-way analysis of variance (ANOVA), P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. For IL-1 and VEGF, P < 0.05 for diet effect and AAV effect. For MCP-1, P < 0.05 for diet effect.

In the HFD group, overexpression of FST significantly decreased serum levels of several adipokines including insulin, leptin, resistin, and C-peptide as compared to GFP-treated mice (Fig. 1C). HFD-FST mice also had significantly lower serum levels of glucose, triglycerides, cholesterol, and free FAs (FFAs) (Fig. 1D), as well as the inflammatory cytokine interleukin-1 (IL-1) (Fig. 1E) when compared to HFD-GFP mice. For both dietary groups, AAV-FST delivery significantly increased circulating levels of vascular endothelial growth factor (VEGF) while significantly decreasing IL-1 levels. Furthermore, obesity-induced inflammation in adipose tissue was verified by the presence of CD11b+CD11c+ M1 pro-inflammatory macrophages or dendritic cells (Fig. 1F).

To determine whether FST gene therapy can mitigate injury-induced OA, mice underwent surgery for destabilization of the medial meniscus (DMM) and were sacrificed 12 weeks after surgery. Cartilage degeneration was significantly reduced in DMM joints of the mice receiving FST gene therapy in both dietary groups (Fig. 2, A and C) when compared to GFP controls. FST overexpression also significantly decreased joint synovitis (Fig. 2, B and D) when compared to GFP controls. To evaluate the local influence of pro-inflammatory cytokines to joint degeneration and inflammation, synovial fluid (SF) was harvested from surgical and ipsilateral nonsurgical limbs and analyzed using a multiplexed array. The DMM joints from mice with FST overexpression exhibited a trend toward lower levels of pro-inflammatory cytokines, including IL-1, IL-1, and IL-6, and a higher level of interferon- (IFN-)induced protein (IP-10) in the SF of DMM joints as compared to contralateral controls (Fig. 2E).

(A) Histologic analysis of OA severity via Safranin O (glycosaminoglycans) and fast green (bone and tendon) staining of DMM-operated joints. (B) Histology [hematoxylin and eosin (H&E) staining] of the medial femoral condyle of DMM-operated joints. Thickened synovium (S) from HFD mice with a high density of infiltrated cells was observed (arrows). (C) Modified Mankin scores compared within the diet. (D) Synovitis scores compared within the diet. (E) Levels of proinflammatory cytokines in the SF compared within the diet. (F) Hot plate latency time and sensitivity to cold plate exposure, as measured using the number of jumps in 30 s, both for non-operated algometry measurements of pain sensitivity compared within the diet. Data are presented as mean SEM; n = 5 to 10 mice per group; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis.

To investigate the effect of FST on pain sensitivity in OA, animals were subjected to a variety of pain measurements including hot plate, cold plate, and algometry. Obesity increased heat withdrawal latency, which was rescued by FST overexpression (Fig. 2F). Cold sensitivity trended lower with obesity, and because no significant differences in heat withdrawal latency were found with surgery (fig. S2), no cold sensitivity was measured after surgery. We found that FST treatment protected HFD animals from mechanical algesia at the knee receiving DMM surgery, while Control-diet DMM groups demonstrated increased pain sensitivity following joint injury.

A bilinear regression model was used to elucidate the relationship among OA severity, biomechanical factors, and metabolic factors (table S1). Factors significantly correlated with OA were then selected for multivariate regression (Table 1). Both multivariate regression models revealed serum tumor necrosis factor- (TNF-) levels as a major predictor of OA severity.

, standardized coefficient. ***P < 0.001.

We analyzed the effects of FST treatment on muscle structure and mass, and performance measures were conducted on mice in both dietary groups. Both Control-FST and HFD-FST limbs exhibited visibly larger muscles compared to both AAV-GFP groups (Fig. 3A). In addition, the muscle masses of tibialis anterior (TA), gastrocnemius, and quadriceps increased significantly with FST treatment (Fig. 3B). Western blot analysis confirmed an increase in FST expression in the muscle at the protein level in FST-treated groups compared to GFP-treated animals in Control and HFD groups (Fig. 3C). Immunofluorescence labeling showed increased expression of FST in muscle (Fig. 3D) and adipose tissue (Fig. 3E) of the AAV-FST mice, with little or no expression of FST in control groups.

(A) Photographic images and (B) measured mass of tibialis anterior (TA), gastrocnemius (GAS), and quadriceps (QUAD) muscles; n = 8, diet and AAV effects both P < 0.05. (C) Western blot showing positive bands of FST protein only in FST-treated muscles, with -actin as a loading control. Immunolabeling of (D) GAS muscle and (E) adipose tissue showing increased expression of FST, particularly in skeletal muscle. (F) H&E-stained sections of GAS muscles were measured for (G) mean myofiber diameter; n = 100 from four mice per group, diet, and AAV effects; both P < 0.05. (H) Oil Red O staining was analyzed for (I) optical density values of FAs; n = 6. (J) Second-harmonic generation imaging of collagen in TA sections was quantified for intensity; n = 6. (K) Western blotting showing the level of phosphorylation markers of protein synthesis in GAS muscle. (L) Functional analysis of grip strength and treadmill time to exhaustion; n = 10. Data are presented as mean SEM; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. Photo credit: Ruhang Tang, Washington University.

To determine whether the increases in muscle mass reflected muscle hypertrophy, gastrocnemius muscle fiber diameter was measured in H&E-stained sections (Fig. 3F) at 28 weeks of age. Mice with FST overexpression exhibited increased fiber diameter (i.e., increased muscle hypertrophy) relative to the GFP-expressing mice in both diet treatments (Fig. 3G). Oil Red O staining was used to determine the accumulation of neutral lipids in muscle (Fig. 3H). We found that HFD-FST mice were protected from lipid accumulation in muscles compared to HFD-GFP mice (Fig. 3I). Second-harmonic generation imaging confirmed the presence of increased collagen content in the muscles of HFD mice, which was prevented by FST gene therapy (Fig. 3J). We also examined the expression and phosphorylation levels of the key proteins responsible for insulin signaling in muscles. We observed increased phosphorylation of AktS473, S6KT389, and S6RP-S235/2369 and higher expression of peroxisome proliferatoractivated receptor coactivator 1- (Pgc1-) in muscles from FST mice compared to GFP mice, regardless of diet (Fig. 3K). In addition to the improvements in muscle structure with HFD, FST-overexpressing mice also showed improved function, including higher grip strength and increased treadmill running endurance (Fig. 3L), compared to GFP mice.

Because FST has the potential to influence cardiac muscle and skeletal muscle, we performed a detailed evaluation on the effect of FST overexpression on cardiac function. Echocardiography and short-axis images were collected to visualize the left ventricle (LV) movement during diastole and systole (fig. S3A). While the Control-FST mice had comparable LV mass (LVM) and left ventricular posterior wall dimensions (LVPWD) with Control-GFP mice (fig. S3, B and C), the HFD-FST mice have significantly decreased LVM and trend toward decreased LVPWD compared to HFD-GFP. Regardless of the diet treatments, FST overexpression enhanced the rate of heart weight/body weight (fig. S3D). Although Control-FST mice had slightly increased dimensions of the interventricular septum at diastole (IVSd) compared to Control-GFP (fig. S3E), there was significantly lower IVSd in HFD-FST compared to HFD-GFP. In addition, we found no difference in fractional shortening among all groups (fig. S3F). Last, transmitral blood flow was investigated using pulse Doppler. While there was no difference in iso-volumetric relaxation time (IVRT) in Control groups, HFD-FST mice had a moderate decrease in IVRT compared to HFD-GFP (fig. S3G). Overall, FST treatment mitigated the changes in diastolic dysfunction and improved the cardiac relaxation caused by HFD.

DXA demonstrated that FST gene therapy improved bone mineral density (BMD) in HFD compared to other groups (Fig. 1B). To determine the effects of injury, diet intervention, and overexpression of FST on bone morphology, knee joints were evaluated by microcomputed tomography (microCT) (Fig. 4A). The presence of heterotopic ossification was observed throughout the GFP knee joints, whereas FST groups demonstrated a reduction or an absence of heterotopic ossification. FST overexpression significantly increased the ratio of bone volume to total volume (BV/TV), BMD, and trabecular number (Tb.N) of the tibial plateau in animals, regardless of diet treatment (Fig. 4B). Joint injury generally decreased bone parameters in the tibial plateau, particularly in Control-diet mice. In the femoral condyle, BV/TV and Tb.N were significantly increased in mice with FST overexpression in both diet types, while BMD was significantly higher in HFD-FST compared to HFD-GFP mice (Fig. 4B). Furthermore, AAV-FST delivery significantly increased trabecular thickness (Tb.Th) and decreased trabecular space (Tb.Sp) in the femoral condyle of HFD-FST compared to HFD-GFP animals (fig. S4).

(A) Three-dimensional (3D) reconstruction of microCT images of non-operated and DMM-operated knees. (B) Tibial plateau (TP) and femoral condyle (FC) regional analyses of trabecular bone fraction bone volume (BV/TV), BMD, and trabecular number (Tb.N). Data are presented as mean SEM; n = 8 to 19 mice per group; two-way ANOVA. (C) 3D microCT reconstruction of metaphysis region of DMM-operated joints. (D) Analysis of metaphysis BV/TV, Tb.N, and BMD. (E) 3D microCT reconstruction of cortical region of DMM-operated joints. (F) Analysis of cortical cross-sectional thickness (Ct.Cs.Th), polar moment of inertia (MMI), and tissue mineral density (TMD). (D and F) Data are presented as mean SEM; n = 8 to 19 mice per group; Mann-Whitney U test, *P < 0.05.

Further microCT analysis was conducted on the trabecular (Fig. 4C) and cortical (Fig. 4E) areas of the metaphyses. FST gene therapy significantly increased BV/TV, Tb.N, and BMD in the metaphyses regardless of the diet (Fig. 4D). Furthermore, FST delivery significantly increased the cortical cross-sectional thickness (Ct.Cs.Th) and polar moment of inertia (MMI) of mice on both diet types, as well as tissue mineral density (TMD) of cortical bones of mice fed control diet (Fig. 4F).

To elucidate the possible mechanisms by which FST mitigates inflammation, we examined the browning/beiging process in subcutaneous adipose tissue (SAT) with immunohistochemistry (Fig. 5A). Here, we found that key proteins expressed mainly in brown adipose tissue (BAT) (PGC-1, PRDM16, thermogenesis marker UCP-1, and beige adipocyte marker CD137) were up-regulated in SAT of the mice with FST overexpression (Fig. 5B). Increasing evidence suggests that an impaired mitochondrial oxidative phosphorylation (OXPHOS) system in white adipocytes is a hallmark of obesity-associated inflammation (17). Therefore, we further examined the mitochondrial respiratory system in SAT. HFD reduced the amount of OXPHOS complex subunits (Fig. 5C). We found that proteins involved in OXPHOS, including subunits of complexes I, II, and III of mitochondria OXPHOS complex, were significantly up-regulated in AAV-FSToverexpressing animals compared to AAV-GFP mice (Fig. 5D).

(A) Immunohistochemistry of UCP-1 expression in SAT. Scale bar, 50 m. (B) Western blotting of SAT for key proteins expressed in BAT, with -actin as a loading control. (C) Western blot analysis of mitochondria lysates from SAT for OXPHOS proteins using antibodies against subunits of complexes I, II, III, and IV and adenosine triphosphate (ATP) synthase. (D) Change of densitometry quantification normalized to the average FST level of each OXPHOS subunit. Data are presented as mean SEM; n = 3. *P < 0.05, t test comparison within each pair.

Our findings demonstrate that a single injection of AAV-mediated FST gene therapy ameliorated systemic metabolic dysfunction and mitigated OA-associated cartilage degeneration, synovial inflammation, and bone remodeling occurring with joint injury and an HFD. Of note, the beneficial effects were observed across multiple tissues of the joint organ system, underscoring the value of this potential treatment strategy. The mechanisms by which obesity and an HFD increase OA severity are complex and multifactorial, involving increased systemic metabolic inflammation, joint instability and loss of muscle strength, and synergistic interactions between local and systemic cytokines (4, 6). In this regard, the therapeutic consequences of FST gene therapy also appear to be multifactorial, involving both direct and indirect effects such as increased muscle mass and metabolic activity to counter caloric intake and metabolic dysfunction resulting from an HFD while also promoting adipose tissue browning. Furthermore, FST may also serve as a direct inhibitor of growth factors in the TGF- family that may be involved in joint degeneration (18).

FST gene therapy showed a myriad of notable beneficial effects on joint degeneration following joint injury while mitigating HFD-induced obesity. These data also indirectly implicate the critical role of muscle integrity in the onset and progression of post-traumatic OA in this model. It is important to note that FST gene therapy mitigated many of the key negative phenotypic changes previously associated with obesity and OA, including cartilage structural changes as well as bone remodeling, synovitis, muscle fibrosis, and increased pain, as compared to GFP controls. To minimize the number of animals used, we did not perform additional controls with no AAV delivery; however, our GFP controls showed similar OA changes as observed in our previous studies, which did not involve any gene delivery (2). Mechanistically, FST restored to control levels a number of OA-associated cytokines and adipokines in the serum and the SF. While the direct effects of FST on chondrocytes remains to be determined, FST has been shown to serve as a regulator of the endochondral ossification process during development (19), which may also play a role in OA (20). Furthermore, previous studies have shown that a 2-week FST treatment of mouse joints is beneficial in reducing infiltration of inflammatory cells into the synovial membrane (15). Our findings suggest that FST delivery in skeletally mature mice, preceding obesity-induced OA changes, substantially reduces the probability of tissue damage.

It is well recognized that FST can inhibit the activity of myostatin and activin, both of which are up-regulated in obesity-related modalities and are involved in muscle atrophy, tissue fibrosis, and inflammation (21). Consistent with previous studies, our results show that FST antagonizes the negative regulation of myostatin in muscle growth, reducing adipose tissue content in animals. Our observation that FST overexpression decreased inflammation at both serum systemic and local joint inflammation may provide mechanistic insights into our findings of mitigated OA severity in HFD-fed mice. Our statistical analysis implicated serum TNF- levels as a major factor in OA severity, consistent with previous studies linking obesity and OA in mice (22). Although the precise molecular mechanisms of FST in modulating inflammation remain unclear, some studies postulate that FST may act like acute-phase protein in lipopolysaccharide-induced inflammation (23).

In addition to these effects of skeletal muscle, we found that FST gene therapy normalized many of the deleterious changes of an HFD on cardiac function without causing hypertrophy. These findings are consistent with previous studies showing that, during the process of aging, mice with myostatin knockout had an enhanced cardiac stress response (24). Furthermore, FST has been shown to regulate activin-induced cardiomyocyte apoptosis (1). In the context of this study, it is also important to note that OA has been shown to be a serious risk factor for progression of cardiovascular disease (25), and severity of OA disability is associated with significant increases in all-cause mortality and cardiovascular events (26).

FST gene therapy also rescued diet- and injury-induced bone remodeling in the femoral condyle, as well as the tibial plateau, metaphysis, and cortical bone of the tibia, suggesting a protective effect of FST on bone homeostasis of mice receiving an HFD. FST is a known inhibitor of bone morphogenetic proteins (BMPs), and thus, the interaction between the two proteins plays an essential role during bone development and remodeling. For example, mice grown with FST overexpression via global knock-in exhibited an impaired bone structure (27). However, in adult diabetic mice, FST was shown to accelerate bone regeneration by inhibiting myostatin-induced osteoclastogenesis (28). Furthermore, it has been reported that FST down-regulates BMP2-driven osteoclast activation (29). Therefore, the protective role of FST on obesity-associated bone remodeling, at least in part, may result from the neutralizing capacity of FST on myostatin in obesity. In addition, improvement in bone quality in FST mice may be explained by their enhanced muscle mass and strength, as muscle mass can dominate the process of skeletal adaptation, and conversely, muscle loss correlates with reduced bone quality (30).

Our results show that FST delivery mitigated pain sensitivity in OA joints, a critical aspect of clinical OA. Obesity and OA are associated with both chronic pain and pain sensitization (31), but it is important to note that structure and pain can be uncoupled in OA (32), necessitating the measurement of both behavioral and structural outcomes. Of note, FST treatment protected only HFD animals from mechanical algesia at the knee post-DMM surgery and also rescued animals from pain sensitization induced by HFD in both the DMM and nonsurgical limb. The mitigation in pain sensitivity observed here with FST treatment may also be partially attributed to the antagonistic effect of FST on activin signaling. In addition to its role in promoting tissue fibrosis, activin A has been shown to regulate nociception in a manner dependent on the route of injection (33, 34). It has been shown that activin can sensitize the transient receptor potential vanilloid 1 (TRPV1) channel, leading to acute thermal hyperalgesia (33). However, it is also possible that activin may induce pain indirectly, for example, by triggering neuroinflammation (35), which could lead to sensitization of nociceptors.

The earliest detectable abnormalities in subjects at risk for developing obesity and type 2 diabetes are muscle loss and accumulation of excess lipids in skeletal muscles (4, 36), accompanied by impairments in nuclear-encoded mitochondrial gene expression and OXPHOS capacity of muscle and adipose tissues (17). PGC-1 activates mitochondrial biogenesis and increases OXPHOS by increasing the expression of the transcription factors necessary for mitochondrial DNA replication (37). We demonstrated that FST delivery can rescue low levels of OXPHOS in HFD mice by increasing expression PGC-1 (Fig. 3H). It has been reported that high-fat feeding results in decreased PGC-1 and mitochondrial gene expression in skeletal muscles, while exercise increases the expression of PGC-1 in both human and rodent muscles (38, 39). Although the precise molecular mechanism by which FST promotes PGC-1 expression has not been established, the infusion of lipids decreases expression of PGC-1 and nuclear-encoded mitochondrial genes in muscles (40). Thus, decreased lipid accumulation in muscle by FST overexpression may provide a plausible explanation for the restored PGC-1 in the FST mice. These findings were further confirmed by the metabolic profile, showing reduced serum levels of triglycerides, glucose, FFAs, and cholesterol (Fig. 1D), and are consistent with previous studies, demonstrating that muscles with high numbers of mitochondria and oxidative capacity (i.e., type 1 muscles with high levels of PGC-1 expression) are protected from damage due to an HFD (4).

In addition, we found increased phosphorylation of protein kinase B (Akt) on Ser473 in the skeletal muscle of FST-treated mice as compared to untreated HFD counterparts (Fig. 3K), consistent with restoration of a normal insulin response. A number of studies have demonstrated that the serine-threonine protein kinase Akt1 is a critical regulator of cellular hypertrophy, organ size, and insulin signaling (41). Muscle hypertrophy is stimulated both in vitro and in vivo by the expression of constitutively active Akt1 (42, 43). Furthermore, it has been demonstrated that constitutively active Akt1 also promotes the production of VEGF (44).

BAT is thought to be involved in thermogenesis rather than energy storage. BAT is characterized by a number of small multilocular adipocytes containing a large number of mitochondria. The process in which white adipose tissue (WAT) becomes BAT, called beiging or browning, is postulated to be protective in obesity-related inflammation, as an increase in BAT content positively correlates with increased triglyceride clearance, normalized glucose level, and reduced inflammation. Our study shows that AAV-mediated FST delivery serves as a very promising approach to induce beiging of WAT in obesity. A recent study demonstrated that transgenic mice overexpressing FST exhibited an increasing amount of BAT and beiging in subcutaneous WAT with increased expression of key BAT-related markers including UCP-1 and PRDM16 (45). In agreement with previous reports, our data show that Ucp1, Prdm16, Pgc1a, and Cd167 are significantly up-regulated in SAT of mice overexpressing FST in both dietary interventions. FST has been recently demonstrated to play a crucial role in modulating obesity-induced WAT expansion by inhibiting TGF-/myostatin signaling and thus promoting overexpression of these key thermogenesis-related genes. Together, these findings suggest that the observed reduction in systemic inflammation in our model may be partially explained by FST-mediated increased process of browning/beiging.

In conclusion, we show that a single injection of AAV-mediated FST, administered after several weeks of HFD feeding, mitigated the severity of OA following joint injury, and improved muscle performance as well as induced beiging of WAT, which together appeared to decrease obesity-associated metabolic inflammation. These findings provide a controlled model for further examining the differential contributions of biomechanical and metabolic factors to the progression of OA with obesity or HFD. As AAV gene therapy shows an excellent safety profile and is currently in clinical trials for a number of conditions, such an approach may allow the development of therapeutic strategies not only for OA but also, more broadly, for obesity and associated metabolic conditions, including diseases of muscle wasting.

All experimental procedures were approved by and conducted in accordance with the Institutional Animal Care and Use Committee guidelines of Washington University in Saint Louis. The overall timeline of the study is shown in fig. S1A. Beginning at 5 weeks of age, C57BL/6J mice (The Jackson Laboratory) were fed either Control or 60% HFD (Research Diets, D12492). At 9 week of age, mice received AAV9-mediated FST or GFP gene delivery via tail vein injection. A total of 64 mice with 16 mice per dietary group per AAV group were used. DMM was used to induce knee OA in the left hind limbs of the mice at the age of 16 weeks. The non-operated right knees were used as contralateral controls. Several behavioral activities were measured during the course of the study. Mice were sacrificed at 28 weeks of age to evaluate OA severity, joint inflammation, and joint bone remodeling.

Mice were weighed biweekly. The body fat content and BMD of the mice were measured using a DXA (Lunar PIXImus) at 14 and 26 weeks of age, respectively.

Complementary DNA synthesis for mouse FST was performed by reverse transcriptase in a reverse transcription quantitative polymerase chain reaction (RT-qPCR) ( Invitrogen) mixed with mRNAs isolated from the ovary tissues of C57BL/6J mouse. The PCR product was cloned into the AAV9-vector plasmid (pTR-UF-12.1) under the transcriptional control of the chicken -actin (CAG) promoter including cytomegalovirus (CMV) enhancers and a large synthetic intron (fig. S1B). Recombinant viral vector stocks were produced at Hope Center Viral Vectors Core (Washington University, St. Louis) according to the plasmid cotransfection method and suspension culture. Viral particles were purified and concentrated. The purity of AAV-FST and AAV-GFP was evaluated by SDSpolyacrylamide gel electrophoresis (PAGE) and stained by Coomassie blue. The results showed that the AAV protein components in 5 1011 vector genomes (vg) are only stained in three major protein bands: VR1, 82 kDa; VR2, 72 kDa; and VR3, 62 kDa. Vector titers were determined by the DNA dot-blot and PCR methods and were in the range of 5 1012 to 1.5 1013 vector copies/ml. AAV was delivered at a final dose of 5 1011 vg per mouse by intravenous tail injection under red light illumination at 9 weeks of age. This dose was determined on the basis of our previous studies showing that AAV9-FST gene delivery by this route resulted in a doubling of muscle mass at a dose of 2.5 1011 vg in 4-week-old mice or at 5 1011 vg in 8-week-old mice (46).

At 16 weeks of age, mice underwent surgery for the DMM to induce knee OA in the left hindlimb as previously described (2). Briefly, anesthetized mice were placed on a custom-designed device, which positioned their hindlimbs in 90 flexion. The medial side of the joint capsule was opened, and the medial meniscotibial ligament was transected. The joint capsule and subcutaneous layer of the skin were closed with resorbable sutures.

Mice were sacrificed at 28 weeks of age, and changes in joint structure and morphology were assessed using histology. Both hindlimbs were harvested and fixed in 10% neutral-buffered formalin (NBF). Limbs were then decalcified in Cal-Ex solution (Fisher Scientific, Pittsburgh, PA, USA), dehydrated, and embedded in paraffin. The joint was sectioned in the coronal plane at a thickness of 8 m. Joint sections were stained with hematoxylin, fast green, and Safranin O to determine OA severity. Three blinded graders then assessed sections for degenerative changes of the joint using a modified Mankin scoring system (2). Briefly, this scoring system measures several aspects of OA progression (cartilage structure, cell distribution, integrity of tidemark, and subchondral bone) in four joint compartments (medial tibial plateau, medial femoral condyle, lateral tibial plateau, and lateral femoral condyle), which are summed to provide a semiquantitative measure of the severity of joint damage. To assess the extent of synovitis, sections were stained with H&E to analyze infiltrated cells and synovial structure. Three independent blinded graders scored joint sections for synovitis by evaluating synovial cell hyperplasia, thickness of synovial membrane, and inflammation in subsynovial regions in four joint compartments, which were summed to provide a semiquantitative measure of the severity of joint synovitis (2). Scores for the whole joint were averaged among graders.

Serum and SF from the DMM and contralateral control limbs were collected, as described previously (2). For cytokine and adipokine levels in the serum and SF fluid, a multiplexed bead assay (Discovery Luminex 31-Plex, Eve Technologies, Calgary, AB, Canada) was used to determine the concentration of Eotaxin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IFN-, IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IP-10, keratinocyte chemoattractant (KC), leukemia inhibitory factor (LIF), liposaccharide-induced (LIX), monocyte chemoattractant protein-1 (MCP-1), M-CSF, monokine induced by gamma interferon (MIG), macrophage inflammatory protein1 (MIP-1), MIP-1, MIP-2, RANTES, TNF-, and VEGF. A different kit (Mouse Metabolic Array) was used to measure levels for amylin, C-peptide, insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, glucagon, insulin, leptin, protein phosphatase (PP), peptide yy (PYY), and resistin. Missing values were imputed using the lowest detectable value for each analyte.

Muscles were cryopreserved by incubation with 2-methylbutane in a steel beaker using liquid nitrogen for 30 s, cryoembedded, and cryosectioned at 8 m thickness. Tissue sections were stained following standard H&E protocol. Photomicrographs of skeletal muscle fiber were imaged under brightfield (VS120, Olympus). Muscle slides fixed in 3.7% formaldehyde were stained with 0.3% Oil Red O (in 36% triethyl phosphate) for 30 min. Images were taken in brightfield (VS120, Olympus). The relative concentration of lipid was determined by extracting the Oil Red O with isopropanol in equally sized muscle sections and quantifying the OD500 (optical density at 500 nm) in a 96-well plate.

To determine spatial expression of FST in different tissues, cryosections of gastrocnemius muscles and adipose tissue were immunolabeled for FST. Tissue sections were fixed in 1.5% paraformaldehyde solution, and primary anti-FST antibody (R&D Systems, AF-669, 1:50) was incubated overnight at 4C after blocking with 2.5% horse serum (Vector Laboratories), followed by labeling with a secondary antibody (Alexa Fluor 488, Invitrogen, A11055) and with 4,6-diamidino-2-phenylindole (DAPI) for cell nuclei. Sections were imaged using fluorescence microscopy.

Second-harmonic generation images of TA were obtained from unstained slices using backscatter signal from an LSM 880 confocal microscope (Zeiss) with Ti:sapphire laser tuned to 820 nm (Coherent). The resulting image intensity was analyzed using ImageJ software.

To measure bone structural and morphological changes, intact hindlimbs were scanned by microCT (SkyScan 1176, Bruker) with an 18-m isotropic voxel resolution (455 A, 700-ms integration time, and four-frame averaging). A 0.5-mm aluminum filter was used to reduce the effects of beam hardening. Images were reconstructed using NRecon software (with 10% beam hardening and 20 ring artifact corrections). Subchondral/trabecular and cortical bone regions were segmented using CTAn automatic thresholding software. Tibial epiphysis was selected using the subchondral plate and growth plate as references. Tibial metaphysis was defined as the 1-mm region directly below the growth plate. The cortical bone analysis was performed in the mid-shaft (4 mm below the growth plate with a height of 1 mm). Hydroxyapatite calibration phantoms were used to calibrate bone density values (mg/cm3).

Fresh visceral adipose tissues were collected, frozen in optimal cutting temperature compound (OCT), and cryosectioned at 5-m thickness. Tissue slides were then acetone-fixed followed by incubation with Fc receptor blocking in 2.5% goat serum (Vector Laboratories) and incubation with primary antibodies cocktail containing anti-CD11b:Alexa Fluor 488 and CD11c:phycoerythrin (PE) (BioLegend). Nuclei were stained with DAPI. Samples were imaged using fluorescence microscopy (VS120, Olympus).

Adipose tissues were fixed in 10% NBF, paraffin-embedded, and cut into 5-m sections. Sections were deparaffinized, rehydrated, and stained with H&E. Immunohistochemistry was performed by incubating sections (n = 5 per each group) with the primary antibody (antimUCP-1, U6382, Sigma), followed by a secondary antibody conjugated with horseradish peroxidase (HRP). Chromogenic substrate 3,3-diaminobenzidine (DAB) was used to develop color. Counterstaining was performed with Harris hematoxylin. Sections were examined under brightfield (VS120, Olympus).

Proteins of the muscle or fat tissue were extracted using lysis buffer containing 1% Triton X-100, 20 mM tris-HCl (pH 7.5), 150 mM NaCl, 1 mm EDTA, 5 mM NaF, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM Na3VO4, leupeptin (1 g ml1), 0.1 mM phenylmethylsulfonyl fluoride, and a cocktail of protease inhibitors (Sigma, St. Louis, MO, USA, catalog no. P0044). Protein concentrations were measured with Quick Start Bradford Dye Reagent (Bio-Rad). Twenty micrograms of each sample was separated in SDS-PAGE gels with prestained molecular weight markers (Bio-Rad). Proteins were wet-transferred to polyvinylidene fluoride membranes. After incubating for 1.5 hours with a buffer containing 5% nonfat milk (Bio-Rad #170-6404) at room temperature in 10 mM tris-HCl (pH 7.5), 100 mM NaCl, and 0.1% Tween 20 (TBST), membranes were further incubated overnight at 4C with antiUCP-1 rabbit polyclonal antibody (1:500, Sigma, U6382), anti-PRDM16 rabbit antibody (Abcam, ab106410), anti-CD137 rabbit polyclonal antibody (1:1000, Abcam, ab203391), total OXPHOS rodent western blot (WB) antibodies (Abcam, ab110413), anti-actin (Cell Signaling Technology, 13E5) rabbit monoclonal antibody (Cell Signaling Technology, 4970), followed by HRP-conjugated secondary antibody incubation for 30 min. A chemiluminescent detection substrate (Clarity, Western ECL) was applied, and the membranes were developed (iBrightCL1000).

The effects of HFD and FST gene therapy on thermal hyperalgesia were examined at 15 weeks of age. Mice were acclimatized to all equipment 1 day before the onset of testing, as well as a minimum of 30 min before conducting each test. Thermal pain tests were measured in a room set to 25C. Peripheral thermal sensitivity was determined using a hot/cold analgesia meter (Harvard Apparatus, Holliston, MA, USA). For hot plate testing, the analgesia meter was set to 55C. To prevent tissue damage, a maximum cutoff time of 20 s was established a priori, at which time an animal would be removed from the plate in the absence of pain response, defined as paw withdrawal or licking. Animals were tested in the same order three times, allowing each animal to have a minimum of 30 min between tests. The analgesia meter was cleaned with 70% ethanol between trials. The average of the three tests was reported per animal. To evaluate tolerance to cold, the analgesia meter was set to 0C. After 1-hour rest, animals were tested for sensitivity to cold over a single 30-s exposure. The number of jumps counted per animal was averaged within each group and compared between groups.

Pressure-pain tests were conducted at the knee using a Small Animal Algometer (SMALGO, Bioseb, Pinellas Park, FL, USA). Surgical and nonsurgical animals were evaluated over serial trials on the lateral aspect of the experimental and contralateral knee joints. The average of three trials per limb was calculated for each limb. Within each group, the pain threshold of the DMM limb versus non-operated limb was compared using a t test run on absolute values of mechanical pain sensitivity for each limb, P 0.05.

To assess the effect of HFD and AAV-FST treatments on neuromuscular function, treadmill running to exhaustion (EXER3, Columbus Instruments) was performed at 15 m/min, with 5 inclination angle on the mice 4 months after gene delivery. Treadmill times were averaged within groups and compared between groups.

Forelimb grip strength was measured using Chatillon DFE Digital Force Gauge (Johnson Scale Co.) for front limb strength of the animals. Each mouse was tested five times, with a resting period of 90 s between each test. Grip strength measurements were averaged within groups and compared between groups.

Cardiac function of the mice was examined at 6 months of age (n = 3) using echocardiography (Vevo 2100 High-Resolution In Vivo Imaging System, VisualSonics). Short-axis images were taken to view the LV movement during diastole and systole. Transmitral blood flow was observed with pulse Doppler. All data and images were performed by a blinded examiner and analyzed with an Advanced Cardiovascular Package Software (VisualSonics).

Detailed statistical analyses are described in methods of each measurement and its corresponding figure captions. Analyses were performed using GraphPad Prism, with significance reported at the 95% confidence level.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This study was supported, in part, by NIH grants AR50245, AR48852, AG15768, AR48182, AG46927, AR073752, OD10707, AR060719, AR074992, and AR75899; the Arthritis Foundation; and the Nancy Taylor Foundation for Chronic Diseases. Author contributions: R.T. and F.G. developed the concept of the study; R.T., N.S.H., C.-L.W., K.H.C., and Y.-R.C. collected and analyzed data; S.J.O. analyzed data; and all authors contributed to the writing of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Many people who practice yoga favor the Sattvic diet given its roots in Ayurveda, a medicinal system that originated in India over 5,000 years ago (1).

Followers of the Sattvic diet primarily consume nutritious foods, including fresh produce and nuts, which is why this diet may lead to a number of health benefits. However, its quite restrictive, and many healthy foods are off-limits.

This article covers everything you need to know about the Sattvic diet, including its associated health benefits and potential downsides, foods to eat and avoid, and a 3-day sample menu.

The Sattvic diet is a high fiber, low fat vegetarian diet followed by many yoga enthusiasts.

In the practice of Yoga, there are three types of foods that have varying qualities and health effects: sattvic, rajasic, and tamasic(2).

The word sattvic means pure essence, and sattvic foods are thought to be pure and balanced, offering feelings of calmness, happiness, and mental clarity.

Rajasic foods are described as overly stimulating, and tamasic foods are believed to increase weakness and laziness (2, 3).

Out of the three types, sattvic foods are considered the most nutritious, and Sattvic diets are associated with a high intake of micronutrients. According to Ayurveda, the Sattvic diet is the best choice for promoting longevity, physical strength, and mental health (4).

This may be because Sattvic diets are rich in fresh, nutrient-dense foods, including fruits, vegetables, sprouted whole grains, fresh fruit juices, legumes, nuts, seeds, honey, and herbal teas (4).

Ayurveda recommends eating predominantly Sattvic foods and avoiding rajasic and tamasic foods (4).

Animal proteins, fried foods, stimulants like caffeine, and white sugar are just some of the foods that are excluded when following a Sattvic dietary pattern.

The Sattvic diet is a high fiber, low fat vegetarian diet thats based on Ayurvedic principles.

The Sattvic diet is rich in nutrient-dense foods and low in processed foods. For these reasons, it may offer many health benefits.

The Sattvic diet is based on consuming whole, nutritious foods, including vegetables, fruits, beans, and nuts.

Consuming these whole, nutrient-dense foods can help promote overall health by providing your body with protein, healthy fats, fiber, vitamins, minerals, and antioxidants that are essential for maintaining proper bodily function (5).

The Sattvic diet encourages eating healthy, whole foods and discourages the consumption of fried and processed foods. Diets high in processed foods are known to harm overall health and significantly increase the risk of numerous diseases (6).

Although no research has been conducted on the Sattvic diet specifically, its well known that diets promoting whole, nutrient-dense foods generally reduce the overall risk of developing chronic conditions, including diabetes, heart disease, and certain cancers.

In particular, vegetarian dietary patterns have been shown to offer an impressive protective effect against chronic disease development.

For example, vegetarian diets are associated with significantly lower levels of heart disease risk factors like high blood pressure and high LDL (bad) cholesterol. Additionally, vegetarian dietary patterns may protect against diabetes and colorectal cancer (7, 8, 9).

Whats more, eating the foods that comprise the majority of the Sattvic diet, including beans, vegetables, fruits, and nuts, may decrease your risk of chronic disease and early death by all causes (10, 11, 12).

The Sattvic diet is rich in fiber and plant foods, which may help promote weight loss.

Studies have shown that people who follow vegetarian dietary patterns typically have lower body mass indexes and less body fat, compared with nonvegetarians (7, 13, 14).

Many studies have also shown that vegetarian diets promote weight loss in overweight individuals (15, 16).

This may be due to several factors, including the high fiber content and reduced calorie density of vegetarian diets.

The Sattvic diet is a vegetarian diet thats high in nutritious, whole foods. Eating a diet rich in whole plant foods may reduce your disease risk and promote a healthy body weight.

Although the Sattvic diet offers many benefits, there are some drawbacks to consider.

While the Sattvic diet is rich in nutrient-dense foods, it cuts out many healthy foods.

For example, followers of the Sattvic diet are encouraged to forgo meat, poultry, fish, and eggs all of which are excellent sources of protein, healthy fats, and various micronutrients.

Additionally, the Sattvic diet excludes foods that are considered rajasic or tamasic.

While some foods in these categories, such as high fat fried foods and added sugars, are unhealthy, many of them are not.

Radishes, chili peppers, onions, and mushrooms are just some examples of exceptionally healthy foods that are off-limits on the Sattvic diet simply because they fall into the rajasic or tamasic categories (4, 17, 18, 19, 20).

Coffee, caffeinated tea, and alcohol are also off-limits on the Sattvic diet, which may make this eating pattern difficult to follow for those who enjoy these beverages.

Although the Sattvic diet principles are based on Ayurvedic beliefs, theyre not necessarily based on scientific research. Therefore, some of the restrictions are likely unnecessary.

The Sattvic diet restricts many healthy foods, and its principles arent based on scientific research. The restrictive nature of this diet may make it hard to stick to in the long term.

When following the Sattvic diet, you must eat only approved foods and avoid foods in the rajasic and tamasic categories.

Keep in mind that recommendations regarding what foods are considered Sattvic vary depending on the source, and many sources contradict one another in terms of what foods are allowed.

The following foods can be eaten liberally on the Sattvic diet (4):

The above foods should make up the majority of your intake when following the Sattvic diet. Keep in mind that there are stricter and looser variations of the diet.

Only sattvic foods, such as land and sea vegetables, fruits and fruit juices, legumes, and sprouted grains, may be consumed when following a Sattvic diet.

The Sattvic diet discourages the consumption of foods that are considered rajasic or tamasic.

For this reason, most animal products, highly processed foods, refined sugar, and fried foods are restricted.

The following foods and ingredients should be avoided on the Sattvic diet (4):

Generally, foods that are overly sour, salty, or spicy should be avoided. Additionally, stale foods, such as foods left out overnight, are considered tamasic and should be avoided.

Added sugars, processed foods, meat, eggs, poultry, fried foods, caffeinated beverages, and alcohol are just some of the items that are off-limits when following the Sattvic diet.

A healthy Sattvic diet should include plenty of produce, beans, and whole grains. According to most sources, high quality dairy can be consumed in moderation.

Here is a 3-day Sattvic diet-approved menu.

The Sattvic diet consists of mainly plant-based meals that include whole grains, vegetables, fruits, and beans.

The Sattvic diet is a vegetarian diet thats based on Ayurvedic principles and popular among yoga enthusiasts.

Those who follow a Sattvic dietary pattern should avoid foods considered rajasic or tamasic like meat, eggs, refined sugar, spicy foods, and fried foods.

Although the Sattvic diet includes many healthy foods and may offer some health benefits, its highly restrictive and not based on science. For these reasons, it may be best to follow a less restrictive, plant-centric diet instead.

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Sattvic Diet Review: What It Is, Food Lists, and Menu - Healthline

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