October 27, 2016

New molecule may help fight obesity by converting 'bad' fat to 'good' fat

Research suggests that activation of a chemical called Beta-LGND2 by the estrogen receptor Beta (ER-Beta) reduces obesity and metabolic diseases in mice by converting bad fat (white fat) to good fat (brown fat). This is significant as brown fat increases metabolism and may facilitate weight loss.

"Although there is a general misperception that obesity is not a life-threatening condition, obesity is the underlying cause for several diseases that could result in mortality," said Ramesh Narayanan, Ph.D., M.B.A., a researcher involved in the work from the Department of Medicine and Director of the Center for Cancer Drug Discovery at the University of Tennessee Health Science Center in Memphis, Tennessee. "Safe and effective treatment for obesity is highly needed, and targeting ER-β might be one of the strategies to safely combat obesity."

To make their discovery, Narayanan and colleagues used three groups of mice. One group was fed with normal rodent diet, while two groups were fed with high-fat diet (HFD) to make them obese. One of the two HFD-fed groups was treated with vehicle, while the other HFD-fed group was treated with beta-LGND2. Beta-LGND2-treated mice were significantly leaner than the other mice fed an HFD. Beta-LGND2-treated mice had higher body temperature and oxygen consumption, indicating higher metabolism rate.

Faseb Journal - Pharmacologic activation of estrogen receptor β increases mitochondrial function, energy expenditure, and brown adipose tissue


Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-β and its ligands. Estrogen receptor β (ER-β) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-β-selective ligand increased markers of tricarboxylic acid–dependent and –independent energy biogenesis and oxygen consumption in mice without a concomitant increase in physical activity or food consumption, all culminating in significantly reduced weight gain and adiposity. The antiobesity effects of ER-β ligand were not observed in ER-β knockout mice. Serum metabolite profiles of adult lean and juvenile mice were comparable, while that of adult obese mice was distinct, indicating a possible impact of obesity on age-dependent metabolism. This phenotype was partially reversed by ER-β-selective ligand. These data highlight a new role for ER-β in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.—Ponnusamy, S., Tran, Q. T., Harvey, I., Smallwood, H. S., Thiyagarajan, T., Banerjee, S., Johnson, D. L., Dalton, J. T., Sullivan, R. D., Miller, D. D., Bridges, D., Narayanan, R. Pharmacologic activation of estrogen receptor β increases mitochondrial function, energy expenditure, and brown adipose tissue.

SOURCES - Faseb Journal, Eurekalert

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