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duminică, 5 august 2012

Hope For New Obesity And Diabetes Treatments From Mechanism That Turns White Fat Into Energy-Burning Brown Fat

Columbia University Medical Center (CUMC) researchers have identified a mechanism that can give energy-storing white fat some of the beneficial characteristics of energy-burning brown fat. The findings, based on studies of mice and of human fat tissue, could lead to new strategies for treating obesity and type 2 diabetes. The study was published in the online edition of the journal Cell.

Humans have two types of fat tissue: white fat, which stores excess energy in the form of triglycerides, and brown fat, which is highly efficient at dissipating stored energy as heat. Newborns have a relative abundance of brown fat, as protection against exposure to cold temperatures. In adults, however, almost all excess energy is stored as white fat.

"Turning white fat into brown fat is an appealing therapeutic approach to staunching the obesity epidemic, but it has been difficult to do so in a safe and effective way," said study leader Domenico Accili, MD, professor of Medicine and the Russell Berrie Foundation Professor at CUMC.

White fat can be "browned" with a class of drugs called thiazolidazines (TZDs), which increase the body's sensitivity to insulin. However, TZDs have many adverse effects - including liver toxicity, bone loss, and, ironically, weight gain - which have limited the use of these drugs.

The current study was undertaken to learn more about the function of TZDs, with the ultimate goal of developing better ways to promote the browning of white fat.

Scientists have known that TZDs promote the browning of white fat by activating a cell receptor called peroxisome proliferator-activated receptor-gamma (ppar-gamma), but the exact mechanism was not clear. To learn more, Dr. Accili and his colleagues studied a group of enzymes called sirtuins, which are thought to affect various biological processes, including metabolism.

The researchers had previously shown in mice that when sirtuin activity increases, so does metabolic activity. In the present study, they found that sirtuins boost metabolism by promoting the browning of white fat. "When we sought to identify how sirtuins promote browning, we observed many similarities between the effect of sirtuins and that of TZDs," said lead author Li Qiang, PhD, associate research scientist in Medicine at CUMC.

Sirtuins work by severing the chemical bonds between acetyl groups and proteins, a process known as deacetylation. "So the next question was whether sirtuins remove acetyl groups from ppar-gamma and, indeed, that was what we found," said Dr. Qiang.

To confirm that the deacetylation of ppar-gamma is crucial to the browning of fat, the researchers created a mutant version of ppar-gamma, in effect mimicking the actions of sirtuins. The mutation promoted the development of brown fat - like qualities in white fat.

"Our findings have two important implications," said Dr. Accili. "First, they suggest that TZDs may not be so bad - if you can find a way to tweak their activity. Second, one way to tweak their activity is by using sirtuin agonists - that is, drugs that promote sirtuin activity."

"The truth is, making sirtuin agonists has proved to be a real bear - more promise than fact," he continued. "But now, for the first time, we have a biomarker for good sirtuin activity: the deacetylation of ppar-gamma. In other words, any substance that deacetylates ppar-gamma should in turn promote the browning of white fat and have a beneficial metabolic effect."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject. Dr. Accili's paper is titled, "Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Ppar-gamma." The other contributors are Ning Kon (CUMC), Wenhui Zhao (CUMC), Sangkyu Lee (University of Chicago, Chicago, Illinois), Yiying Zhang (CUMC), Michael Rosenbaum (CUMC), Yingming Zhao (University of Chicago), Wei Gu (CUMC), and Stephen R. Farmer (Boston University School of Medicine, Boston, Mass.)
This research was supported by grants from the National Institutes of Health (HL087123, DK58282, DK64773, DK063608, and RR024156).
The authors declare no financial or other conflicts of interest.
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joi, 15 decembrie 2011

Ability Of Brown Fat To Burn Calories Linked To Immune Cells

Main Category: Obesity / Weight Loss / Fitness
Article Date: 15 Dec 2011 - 0:00 PST

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Throughout the interior spaces of humans and other warm-blooded creatures is a special type of tissue known as brown fat, which may hold the secret to diets and weight-loss programs of the future.

Unlike ordinary "white" fat, in which the body stores excess calories, brown fat can burn calories to heat up the body. It's one of the things that helps keep wild critters warm on cold nights.

Investigating how brown fat works in mice, a team of researchers at the University of California, San Francisco (UCSF) has uncovered what may be a holdover from our evolutionary past: in response to cold, tiny immune cells known as macrophages can switch on the brown fat, inducing it to burn energy to make heat.

Prior to this research, published last month in the journal Nature, scientists had assumed that brown fat metabolism was completely controlled by the brain. But the UCSF research suggests that the immune system plays a backup role in this process - a legacy, perhaps, of some ancient ancestral creature whose metabolic and immune systems were much more intertwined.

"This is a very important secondary system that the body uses to provide a backup for the thermal stress response," said Ajay Chawla, MD, PhD, an associate professor at UCSF's Cardiovascular Research Institute who led the research. "It raises the possibility that we can perhaps modulate this program and enhance it in humans to rev up metabolism."

Immune Cells Found Inside Brow

The modern human immune system relies on these macrophages to gobble up bacteria, helping protect us against infection. Macrophages were never known to play a role in metabolism, but the evidence Chawla and his colleagues gathered suggests otherwise.

Using brown fat to burn calories and produce heat is one of the ways that mammals maintain thermoregulation - an essential adaptation that defines warm blooded creature and enables them to thrive in the face of challenging environmental extremes. Not all animals share this ability.

Many animals, like lizards, are "cold blooded" or exothermic. They maintain their body temperature through completely external means, sunbathing at certain times of the day and huddling in warm, protective places at night. This naturally limits their range and explains why lizards, so abundant in tropical climates, are far rarer in cold climates.

Mammals, on the other hand, are "warm-blooded" or endothermic. They produce heat internally by a variety of means: shivering, sweating, regulating the size of their blood vessels and burning off excess calories in brown fat.

Scientists have known for years that brown fat burns calories in response to signals from the brain. These signals cause break down of molecules known as triglycerides in white fat, which are then released into the bloodstream as fatty acids. These circulating fatty acids are taken up by brown fat and burned to generate heat. Brown fat is full of blood vessels, and the heat warms the blood, which in turn circulates and warms the body.

The brain controls this process by monitoring the body's temperature and, in face of extreme cold, releasing a hormone called norepinephrine, which kick-starts the brown fat.

The work of the UCSF team showed that macrophage cells within the brown fat can also do this directly. Macrophages residing in brown and white fat produce an enzyme that makes norepinephrine when mice are exposed to the cold. This leads to the production, the breakdown and mobilization of stored fat, which is then burned in brown fat to produce heat.

What these results suggest, Chawla said, is that immune cells help facilitate the function of brown fat.

Mammals today have evolved to have separate systems for immunity and metabolism. But flies, for instance, have combined the equivalent functions of the human liver, fat and immune system into one organ: a tissue referred to as its fat body. Mammalian macrophages may have some functions related to this shared origin.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject. The article, “Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis” by Khoa D. Nguyen, Yifu Qiu, Xiaojin Cui, Y. P. Sharon Goh, Julia Mwangi, Tovo David, Lata Mukundan, Frank Brombacher, Richard M. Locksley and Ajay Chawla appeared in the Nov. 20 issue of Nature.
In addition to UCSF, the authors of this study are affiliated with Stanford University and the University of Cape Town, South Africa.
This work was funded by grants from the National Institutes of Health and the Larry L. Hillblom Foundation; by an National Institutes of Health Director’s Pioneer Award; and by Stanford Graduate and
A-STAR Fellowships.
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