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bioRxiv · 10.1101/310383

HDAC11 Deficiency Prevents High-Fat Diet-Induced Obesity and Metabolic Syndrome

Sun, L.·Marin De Evsikova, C.·Bian, K.·Achille, A.·Telles, E.·Seto, E.
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Abstract

Significance StatementObesity is a serious and widespread health problem which has become a growing concern in many societies. Most currently available weight-loss medications do not work for everyone, and the effects decline over time. Thus, there is an urgent need to identify new molecular targets to improve drug development for the treatment of obesity and obesity-related diseases. In this study, we discovered that the histone deacetylase 11 (HDAC11) enzyme is a key regulator of metabolism and obesity, and the absence of HDAC11 prevents obesity in mice. Our findings will facilitate the development of novel therapeutics to treat obesity by targeting HDAC11.\n\nAbstractObesity and its associated metabolic syndromes are the consequence of susceptible genes and obesogenic environments. We report here that histone deacetylase 11 (HDAC11) plays a critical role in the development of obesity and in metabolic homeostasis. HDAC11 knockout mice display resistance to high-fat diet-induced obesity and associated syndromes by enhancing glucose tolerance and insulin sensitivity, attenuating hypercholesterolemia and hyperinsulinemia, and blocking hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue. Moreover, loss of HDAC11 stimulates mitochondrial oxidation, elevates plasma adiponectin, and activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. These findings establish HDAC11 as a key regulator of metabolism and indicate that HDAC11 inhibitors may hold promise for treating overweight and obesity-related diseases.

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Sun, L., Marin De Evsikova, C., Bian, K., Achille, A., Telles, E., Seto, E.. 2018-04-28. HDAC11 Deficiency Prevents High-Fat Diet-Induced Obesity and Metabolic Syndrome. https://doi.org/10.1101/310383

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