Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis, and Insulin Resistance

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Abstract

Obesity and type 2 diabetes are associated with impaired mitochondrial function in adipose tissue. To study the effects of primary deficiency of mitochondrial energy metabolism in fat, we generated mice with adipose-specific deficiency of fumarate hydratase (FH), an integral Krebs cycle enzyme (AFHKO mice). AFHKO mice have severe ultrastructural abnormalities of mitochondria, ATP depletion in white adipose tissue (WAT) and brown adipose tissue, low WAT mass with small adipocytes, and impaired thermogenesis with large unilocular brown adipocytes. AFHKO mice are strongly protected against obesity, insulin resistance, and fatty liver despite aging and high-fat feeding. AFHKO white adipocytes showed normal lipolysis but low triglyceride synthesis. ATP depletion in normal white adipocytes by mitochondrial toxins also decreased triglyceride synthesis, proportionally to ATP depletion, suggesting that reduced triglyceride synthesis may result nonspecifically from adipocyte energy deficiency. At thermoneutrality, protection from insulin resistance and hepatic steatosis was diminished. Taken together, the results show that under the cold stress of regular animal room conditions, adipocyte-specific FH deficiency in mice causes mitochondrial energy depletion in adipose tissues and protects from obesity, hepatic steatosis, and insulin resistance, suggesting that in cold-stressed animals, mitochondrial function in adipose tissue is a determinant of fat mass and insulin sensitivity.

Footnotes

• This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0136/-/DC1.

• Received January 28, 2016.
• Accepted August 16, 2016.

• © 2016 by the American Diabetes Association.

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January 2017, 66(1) Article Alerts Email Article Citation Tools Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis, and Insulin Resistance Hao Yang, Jiang W. Wu, Shu P. Wang, Ilenia Severi, Loris Sartini, Norma Frizzell, Saverio Cinti, Gongshe Yang, Grant A. Mitchell

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