title: Role of medium- and short-chain L-3-hydroxyacyl-CoA dehydrogenase in the regulation of body weight and thermogenesis.
abstract: Dysregulation of fatty acid oxidation plays a pivotal role in the pathophysiology of obesity and insulin resistance. Medium- and short-chain-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (SCHAD) (gene name, hadh) catalyze the third reaction of the mitochondrial β-oxidation cascade, the oxidation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA, for medium- and short-chain fatty acids. We identified hadh as a putative obesity gene by comparison of two genome-wide scans, a quantitative trait locus analysis previously performed in the polygenic obese New Zealand obese mouse and an earlier described small interfering RNA-mediated mutagenesis in Caenorhabditis elegans. In the present study, we show that mice lacking SCHAD (hadh(-/-)) displayed a lower body weight and a reduced fat mass in comparison with hadh(+/+) mice under high-fat diet conditions, presumably due to an impaired fuel efficiency, the loss of acylcarnitines via the urine, and increased body temperature. Food intake, total energy expenditure, and locomotor activity were not altered in knockout mice. Hadh(-/-) mice exhibited normal fat tolerance at 20 C. However, during cold exposure, knockout mice were unable to clear triglycerides from the plasma and to maintain their normal body temperature, indicating that SCHAD plays an important role in adaptive thermogenesis. Blood glucose concentrations in the fasted and postprandial state were significantly lower in hadh(-/-) mice, whereas insulin levels were elevated. Accordingly, insulin secretion in response to glucose and glucose plus palmitate was elevated in isolated islets of knockout mice. Therefore, our data indicate that SCHAD is involved in thermogenesis, in the maintenance of body weight, and in the regulation of nutrient-stimulated insulin secretion.
authors: Department of Experimental Diabetology and Pharmacology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Nadja
authors: N
authors: Schulz
authors: Heinz
authors: H
authors: Himmelbauer
authors: Michaela
authors: M
authors: Rath
authors: Michel
authors: M
authors: van Weeghel
authors: Sander
authors: S
authors: Houten
authors: Wim
authors: W
authors: Kulik
authors: Karsten
authors: K
authors: Suhre
authors: Stephan
authors: S
authors: Scherneck
authors: Heike
authors: H
authors: Vogel
authors: Reinhart
authors: R
authors: Kluge
authors: Petra
authors: P
authors: Wiedmer
authors: Hans-Georg
authors: HG
authors: Joost
authors: Annette
authors: A
authors: Schürmann
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D044926:Butyryl-CoA Dehydrogenase / Q000502:physiology*; D003080:Cold Temperature; D004734:Energy Metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D022722:Thermogenesis; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; D044926:Butyryl-CoA Dehydrogenase; D042964:Acyl-CoA Dehydrogenase