title: Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis, and Insulin Resistance.
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.
authors.affiliation: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.|Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Jiang W
authors.initials: JW
authors.lastname: Wu
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Shu P
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona (Università Politecnica Delle Marche), Ancona, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Severi
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona (Università Politecnica Delle Marche), Ancona, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Sartini
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC.
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona (Università Politecnica Delle Marche), Ancona, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China grant.mitchell@recherche-ste-justine.qc.ca gsyang999@hotmail.com.
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada grant.mitchell@recherche-ste-justine.qc.ca gsyang999@hotmail.com.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000201:enzymology* / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000201:enzymology* / Q000378:metabolism*; D000818:Animals; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008066:Lipolysis / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D000255:Adenosine Triphosphate; D005649:Fumarate Hydratase