A new study by researchers at the University of Texas Medical Branch in Galveston reveals for the first time that people with higher levels of brown adipose tissue (“brown fat“) in their body tissues have better blood sugar control, higher insulin sensitivity and a better metabolism for burning stored fat.
These findings suggest that brown fat’s capacity to better regulate blood sugar could be utilized as a potential medical weapon against diabetes, and thus may function as an anti-obesity and anti-diabetic tissue in humans.
“We showed that exposure to mild cold raised whole body energy expenditure, increased glucose removal from the circulation and improved insulin sensitivity in men who have significant amounts of brown adipose tissue depots, says UTMB professor of Internal Medicine in the Division of Geriatric Medicine Dr. Labros S. Sidossis, Ph.D. Dr. Sidossis is also affiliated with the Department of Nutrition and Dietetics at Harokopio University in Athens, Greece.
There are two types of fat tissue in the human body: the problematical white fat tissue that causes obesity, and the less familiar brown fat tissue. Another of the many negative health effects of excess white fat tissue is decreased insulin sensitivity — a major contributing factor in development of diabetes. On the other hand, brown fat has several healthy qualities, including protection against obesity and diabetes.
In their new study appearing in the American Diabetes Association journal Diabetes, Dr. Sidossis and his colleagues compared otherwise similar healthy men with either high or low levels of brown fat tissue on their resting energy expenditure, glucose usage and insulin sensitivity. The subjects were placed in either normal temperature conditions or were exposed to mildly cold temperatures for five to eight hours.
The study, published online before print in the July 23, 2014 edition of Diabetes, is entitled “Brown Adipose Tissue Improves Whole Body Glucose Homeostasis and Insulin Sensitivity in Humans” (doi: 10.2337/db14-0746) and coauthored by Maria Chondronikola, Elena Volpi, Elisabet Borsheim, Craig Porter, Palam Annamalai, Sven Enerback, Martin Lidell, Manish Saraf, Sebastien Labbe, Nicholas Hurren, Christina Yfanti, Tony Chao, Clark Andersen, Fernando Cesani and Hal Hawkins and Labros S. Sidossis, variously of tha Metabolism Unit, Shriners Hospital for Children, Galveston; the Departments of Preventive Medicine and Community Health, Nutrition and Metabolism, Division of Rehabilitation Sciences, Institute for Translational Sciences, Sealy Center on Aging, Internal Medicine, Surgery, Interventional Radiology, Nuclear Medicine, and Pathology at the University of Texas Medical Branch, Galveston; the Department of Nutrition and Dietetics, Harokopio University of Athens, Greece; the Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Sweden; the Quebec Heart and Lung Research Institute Centre, Quebec City, Canada; and the Department of Pathology, Shriners Hospital for Children, Galveston.
The researchers note that brown adipose tissue (BAT) has attracted scientific interest as an anti-diabetic tissue owning to its ability to dissipate energy as heat, but that despite a large volume of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans has remained unclear.
To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, the research team studied 7 BAT positive (BAT+) men and 5 BAT negative (BAT-) men under thermoneutral conditions and after prolonged (5-8 h) cold exposure (CE). The two groups were similar in age, body mass index, and adiposity.
Throughout the cold or regular temperature exposure period, the team conducted comprehensive analyses of various bodily samples. They collected blood and breath samples to observe changes in glucose and insulin concentrations, hormone changes, whole body oxygen consumption and carbon dioxide production rates. They also aspirated brown and white fat tissue samples to analyze differences in cellular energy production and gene expression.
CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. The coauthors conclude that these results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an anti-diabetic tissue in humans.
“In this study we show that, when activated via mild cold exposure, brown adipose tissue can increase energy expenditure and burn calories. This is good news for overweight and obese people, says Dr. Sidossis in a UTMB release. “Of even greater clinical significance may be the finding that brown fat can help the body regulate blood sugar more effectively. This is great news for people with insulin resistance and diabetes and suggests that brown fat may prove to be an important anti-diabetic tissue.”
The research project reported in Diabetes was supported by the National Institutes of Health, the American Diabetes Association, UTMB Institute for Translational Sciences, the Shriners Hospitals for Children, the UTMB Claude Pepper Older Americans Independence Center and the UTMB Sealy Center on Aging.
Cold Exposure Stimulates Beneficial Brown Fat Growth
Results of a related study presented June 22 at ICE/ENDO 2014, the joint meeting of the International Society of Endocrinology and the Endocrine Society in Chicago, found that long-term mild cold exposure can stimulate brown fat growth and activity in humans and may benefit glucose and energy metabolism.
The study researchers noted that brown adipose tissue burns energy and glucose to generate heat — a process that keeps small animals and babies warm, and protects animals with abundant brown fat from diabetes and obesity. However the regulation of brown fat in humans and how it relates to metabolism, remain unclear.
“Our research points to a simple and practical brown fat activating and growing strategy in humans through temperature exposure modulation. We show that long-term minimal manipulation of overnight ambient temperature well within the range found in climate-controlled buildings was able to modulate brown fat activity in humans. Mild cold exposure stimulated brown fat activity while mild warm exposure suppressed it. Brown fat increase was accompanied by improvement in insulin sensitivity and energy burning rate after food,” said Paul Lee, MD, PhD, former research fellow at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH).
In their Impact of Chronic Cold Exposure in Humans (ICEMAN) study, Dr. Lee and his colleagues explored the impact of controlled temperature acclimatization on BAT and energy balance by following 5 men between 19 and 23 years of age over a 4-month period. The volunteers engaged in their usual daytime activities but slept in a private room in which the air temperature varied monthly between 66F (19C) and 81F (27C). Personal temperature detectors monitored each volunteer’s exposed temperature continuously over the entire 4 months.
At the end of each month, the researchers measured the men’s BAT and energy metabolism and found that mild cold (19 C) increased the men’s brown fat amount and activity while mild warmth (27 C) suppressed it.
“The improvement in insulin sensitivity accompanying brown fat gain may open new avenues in the treatment of impaired glucose metabolism in the future. On the other hand, the reduction in mild cold exposure from widespread central heating in contemporary society may impair brown fat function and may be a hidden contributor to obesity and metabolic disorders,” says Dr. Lee.
The study authors suggest that recruiting and activating BAT by manipulating temperature may be a promising therapeutic strategy in obesity and diabetes treatment.
Researchers at UT Southwestern Medical Center in Dallas have discovered a protein plays a key role in specific areas of the brain to regulate metabolism by controlling when genes are switched on or off. These findings could potentially be key to developing new therapies to treat obesity and diabetes.
The new work implicates IRE1, the protein kinase that possesses endonuclease activity. IRE1 is important in altering gene expression as a response to endoplasmic reticulum based stress which produces a molecule called spliced X-box binding protein 1 (Xbp1s), as a transcription factor and direct activator of the hexosamine biosynthetic pathway (HBP). The HBP is responsible for producing modified glucose molecules that couple to numerous proteins, leading to beneficial changes in their function, stability, and location within the cell. This coupling, termed O-GlcNAcylation, has favorable effects on disease-injured cells, including myocytes. Xbp1s appears to influence the body’s sensitivity to signsignallingulin and leptin — hormones essential to the body’s regulation of food intake and sugar disposal. Obesity and diabetes are conditions under which the body develops resistance to insulin and leptin’s actions.
In a new study published online in the journal Cell Metabolism entitled “Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis” (DOI: http://dx.doi.org/10.1016/j.cmet.2014.06.002), coauthors Kevin W. Williams, Tiemin Liu, Xingxing Kong, Makoto Fukuda, Yingfeng Deng, Eric D. Berglund, Zhuo Deng, Yong Gao, Tianya Liu, Jong-Woo Sohn, Lin Jia, Teppei Fujikawa, Daisuke Kohno, Michael M. Scott, Syann Lee, Charlotte E. Lee, Kai Sun, Yongsheng Chang, Philipp E. Scherer, and Joel K. Elmquist, all of UT Southwestern, note that Xbp1s in Pomc neurons protects against ER stress-induced leptin/insulin resistance and improves glucose levels and hepatic insulin sensitivity. Pomc-specific xbp1s also protects against high-fat diet-induced obesity, and regulates the UPRER in the liver.
The researchers observe that molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear, and show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress.
They also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes.
“This study identifies critical molecular mechanisms that link the brain and peripheral endocrine tissues and that ultimately contribute to the regulation of body weight and glucose metabolism,” says Dr. Kevin Williams, Assistant Professor of Internal Medicine and co-first author of the study with Dr. Tiemin Liu, a postdoctoral research fellow in Internal Medicine at UTSW.
Dr. Williams’s lab at UTSW uses mouse genetics, electrophysiology, and systems neuroscience approaches to study the cellular mechanisms within the brain which may underlie the coordinated control of food intake, body weight, and glucose homeostasis.
“Manipulating this one gene in the brain affected metabolism in the liver. This result shows that the brain is controlling glucose production by the liver,” says study senior coauthor Dr. Joel Elmquist, Director of the Division of Hypothalamic Research, Professor of Internal Medicine, Pharmacology, and Psychiatry, and holder of the Carl H. Westcott Distinguished Chair in Medical Research, and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley.
Co-senior author of the study is Dr. Philipp Scherer, Director of the Touchstone Center for Diabetes Research, Professor of Internal Medicine and Cell Biology, and holder of the Gifford O. Touchstone Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.
The Elmquist Lab at UT Southwestern’s research focuses on the functional neuroanatomy of the mammalian hypothalamus, focused mainly on regulation of body weight homeostasis, food intake, and control of the autonomic nervous system. The lab’s current projects involve investigating the central mechanisms underlying the actions of leptin, melanocortins, orexin, glucagon-like peptide, and serotonin.
The lab focuses on identifying pathways in the brain involved in regulating autonomic functions, such as body weight regulation, thermoregulation, and cardiovascular control. Homeostasis is maintained by motivated behaviors subserving these basic vital functions. The hypothalamus is critical for regulating each of these processes and behaviors, but the complex hypothalamic circuits that underlie these responses have remained difficult to characterize. Whereas, unraveling these interactions once seemed a far-off goal, progress in the last few years in determining critical genes that regulate body weight has given us tools to dissect the neuronal pathways, neurotransmitters, and physiological responses that result in homeostasis.
The availability of these new molecular tools, coupled with more traditional neuroanatomic techniques including tract tracing and whole animal physiology, has allowed the identification of an extensive network of hypothalamic circuitry that may regulate feeding, insulin secretion, cardiovascular control, and body weight homeostasis.
The Elmquist Lab uses conditional, neuron-specific gene-targeting methods to determine the functional importance of these neurocircuits in controlling body weight. Techniques being utilized include BAC transgenesis, neuron-specific knockouts, neuron-specific gene reactivations, and neuron-specific cell ablation.
Currently, no drug form of Xbp1s is available that could be used to test whether the gene is a target for the treatment of diabetes or obesity, but the researchers project such a drug being a potential outgrowth of their research. Meanwhile other transcription factors involved in the same metabolic pathway will be studied to see if they have similar effects Dr. Williams noting: “We have studied one transcription factor out of many that participate in a large, complex cellular process” referring to of Xbp1s and its role during times of cellular stress.
The study was supported by grants from the National Institutes of Health, American Diabetes Association, American Heart Association, and the Juvenile Diabetes Research Foundation.
University of Texas Medical Branch
UT Southwestern Medical Center
Diabetes (American Diabetes Association journal)
The Endocrine Society
University of Texas Medical Branch
UT Southwestern Medical Center