White Fat, Brown Fat, Bad Fat, Good Fat

For nearly two decades, Sheng Bi and colleagues have been teasing out neural signal pathways in rat brains that transform white fat into calorie-burning brown fat. The research has drawn great interest for its potential to treat obesity and diabetes.
For nearly two decades, Sheng Bi and colleagues have been teasing out neural signal pathways in rat brains that transform white fat into calorie-burning brown fat. The research has drawn great interest for its potential to treat obesity and diabetes.

BrainWise
Summer 2016

When psychiatry researcher Sheng Bi came to Johns Hopkins from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 1999, he studied impaired glucose tolerance in a rat model. In trials comparing the feeding of obese and normal rats, he analyzed gene expression in obese rats with abnormally large appetites or diabetes. But when he looked at tissue from the obese rats’ brains, he noticed something interesting: an increase in the appetite-stimulating neuropeptide Y (NPY) protein.

That chance finding kick-started years of research in the department’s Behavioral Neuroscience Lab, in which Bi and colleagues have been teasing out neural mechanisms underlying the controls of food intake, energy expenditure and glucose regulation.

In a 2011 study in the journal Cell Metabolism that garnered attention from the BBC and NPR, Bi and his team found that knocking down NPY expression in the dorsomedial hypothalamus of the brain—which helps regulate thirst, hunger and body temperature—not only reduced rats’ calorie intake and weight, but also transformed their fat into a type that burns off more energy.

The study looked at two types of fat made by the body: white and brown adipose tissue, or WAT and BAT. WAT is the typical fat that ends up around our middles and other places, and stores the extra calories we eat. These cells have a large droplet of lipid as an energy storage unit. Cells in BAT, considered a “good fat” for its energy-burning qualities, contain many mitochondria (cell powerhouses) and little droplets of lipid, each with its own power source, which generates heat. Babies have ample stores of brown fat at birth to help protect them against cold, but it mostly disappears, so adults have very little of this calorie-burning tissue.

Checking the rats’ fat content after death, Bi was surprised to find brown fat in the groin area of the rats with knocked-down NPY in place of where white fat should be. The transformation may result from an activation of BAT stem cells contained within WAT tissue, he says, so brown fat doesn’t actually disappear with age but becomes inactive.

While the critical role for brown fat in adults in the maintenance of energy balance remains to be determined, Bi says, finding it in adults has “led to a great interest in its potential for treating obesity and diabetes, such as searching for ways to elevate brown fat activity or turning white fat to brown fat that would burn calories instead of storing them.”

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Continuing work by Bi’s team, funded by NIDDK, has found that knocking down NPY can reverse diet-induced obesity and impaired glucose tolerance in rats.

In a study published last fall in the American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, Bi investigated a rat model of high-fat, diet-induced obesity and insulin resistance designed to mimic human obesity with impaired glucose regulation. Rats had free access to either regular or high-fat chow and underwent an oral glucose tolerance test. Then, some received injections of a recombinant virus to knock down NPY expression.

The control group of rats untreated with this recombinant virus remained obese, glucose intolerant and insulin resistant, whereas those treated with the recombinant virus saw a complete reversal of conditions within weeks. They exhibited normal food intake, body weight, glucose tolerance and insulin sensitivity like normal, lean rats. 

NPY expression seen in rats is similar to that observed in primates, Bi says, so if these types of studies can be replicated, the protein expression could serve as a potential target for the treatment of obesity and diabetes in humans.