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March 8, 2015 Did Yale researchers really discover a way to reverse type 2 diabetes, along with fatty liver disease, using a banned agent that had been used in weight loss pills over 70-years ago?
According to a study published by Science (2-26-2015), Yale researchers developed a controlled-release oral therapy that reversed type 2 diabetes and fatty liver disease (in rats). Existing therapies for type 2 diabetes, and the closely associated conditions of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), have had limited success at treating the root causes of these diseases. DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on the drug’s ability to greatly increase metabolic rate. They discovered that DNP’s efficacy in reducing liver fat and liver inflammation could be achieved with plasma concentrations that were more than a 100-fold less than the toxic levels. In the next phase of the study, Shulman and his team developed a new oral, controlled-release form of DNP, known as CRMP, which maintained the drug at concentrations that were more than a 100-fold lower than the toxic threshold.
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Desiree Wanders receives funding from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases.
But white fat isn’t the only kind of fat in the body – you also have brown fat and beige, or brite, fat, which can actually burn calories instead of storing them.
Fat that burns calories instead of packing them on the body sounds like the Holy Grail of obesity treatment, and researchers want to find ways to activate or increase these types of fat in our bodies. You might think that white fat just stores calories, but it actually does much more than that. Newborn babies have brown fat because it generates heat and helps them maintain body temperature.
In humans, brown fat tends to be located around the neck and clavicle, but can also be found in a few other locations around the body. Beige or brite fat is made up of “brown-like” fat cells present in traditionally white fat deposits.
Whether these beige fat cells were preexisting white fat cells that turned into beige cells in a process called “transdifferentiation” or they are brand new cells is a point of contention among researchers.
The principle behind weight loss or weight gain is called energy balance, which is the difference between energy intake (how many calories you eat) and energy expenditure (how many calories you burn). Sticking to a low-calorie diet and an exercise-heavy lifestyle to lose excess weight isn’t always easy, so researchers have been looking for other ways to tip the energy balance in favor of expenditure. Imagine if we could do the same thing in humans and transform the metabolically inert white fat that is weighing so many of us down into metabolically active brown fat that actually burns calories throughout the day.

For instance, some research has shown that activation of brown fat by cold exposure in humans translates to an increase in energy expenditure equivalent to less than 20 calories per day, which is hardly enough to have the kind of effects on obesity that we all hope for. The reason that activated brown fat makes a relatively small contribution to daily energy expenditure is unknown, though it may be because brown fat is present in the body in minuscule amounts compared the less metabolically active white fat. And we also wouldn’t want to convert all of our white fat into brown fat, because white fat is actually something our bodies need.
For instance, in rare conditions in which there are no fat deposits, people often have insulin resistance, fatty liver disease and other metabolic complications.
Even if the data show that activating brown fat doesn’t seem to burn many extra calories in humans, it could have other health benefits.
Researchers found that transplanting brown fat from donor mice into the abdominal cavity of age- and sex-matched recipient mice reversed high-fat diet-induced insulin resistance, a condition that contributes to Type 2 diabetes in humans. Other studies have shown that beige and brown fat has beneficial effects on glucose metabolism and insulin sensitivity that appear to be greater than the modest effects on body weight. So future human research may lie in how these fats can positively influence insulin sensitivity, or glucose and lipid metabolism, rather than body weight.
There is much interest in being able to harvest the power of brown fat in humans to combat obesity and accompanying metabolic disease, but this research is relatively in infancy. To help answer these questions, the NIH has announced grant opportunities to identify conditions that trigger the “browning” of white fat, or increase quantity of brown fat in humans, find ways of testing for brown fat that don’t require needle biopsies, and explore the biological functions of these fats.
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Olaf Alders on Twitter: "My own private research shows that a carefully chosen LinkedIn photo can put an immediate stop to recruiter spam. We use a Creative Commons Attribution NoDerivatives licence, so you can republish our articles for free, online or in print. That’s where our bodies store excess calories, and it’s the stuff you want to get rid of when you are trying to lose weight. In fact, the National Institutes of Health (NIH) has put out a call for research to figure out how to do it.
It insulates the body, protects the internal organs and also produces proteins that regulate food intake, energy expenditure and insulin sensitivity. You may remember from high school science class that mitochondria are the “powerhouses” of the cell because they burn fatty acids and glucose for energy, releasing it as heat.
Weight can influence how active a person’s brown fat is, so the more a person weighs, the less active their brown fat is at burning fatty acids and glucose.

Studies using animal models have shown these beige fat cells can form in white fat deposits under certain treatments, including cold exposure. Like brown fat cells, beige fat cells appear to have the ability to burn fatty acids and glucose as energy. And some think that increasing the activity or quantity of brown or beige fat in the body might be one way of doing it.
Studies have found that the chemical norepinephrine, cold exposure, diets and various proteins made in the body can all induce “browning” of white fat or activate brown fat to burn more calories in rodents.
While it sounds like it could be a game changer in the fight against obesity, the research isn’t clear on how much of a difference brown fat might make for people. Other research has estimated that activation of brown fat in adults could burn up to 125 extra calories per day.
For instance, a recent study showed that out of 14 subjects, only five had more than 10 grams of activated brown fat. This is partially due to the lack of proteins that are produced by the white fat, and also because the excess calories that should be stored in the fat have to be stored in other organs, such as the liver. Brown fat has the ability to clear lipids (fats) and glucose from the blood, resulting in lower concentrations of circulating triglycerides, cholesterol and glucose.
To combat growing obesity, lawmakers have introduced a new campaign encouraging physical activity. For many, parting with sugar is akin to taking monastic vows. But what if diabetics could eat anything and not feel guilty about it? Concerns about dangerous side-effects and rapidly developing cataracts resulted in DNP being discontinued in the United States by the end of 1938. Most of these treatments also have some effect on energy balance, often increasing energy expenditure and causing weight loss. This may contribute to the beneficial health effects of brown fat, independent of weight loss. DNP, however, continues to be used by some bodybuilders and athletes to rapidly lose body fat. This research was supported by grants from the National Institutes of Health (R01 DK-40936, R24 DK-085638, U24 DK-059635, T32 DK-101019, P30 DK-45735, P30 DK-34989 and UL1 TR-000142) and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

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