TY - JOUR
T1 - Role of medium- and short-chain L-3-hydroxyacyl- CoA dehydrogenase in the regulation of body weight and thermogenesis
AU - Schulz, Nadja
AU - Himmelbauer, Heinz
AU - Rath, Michaela
AU - Van Weeghel, Michel
AU - Houten, Sander
AU - Kulik, Wim
AU - Suhre, Karsten
AU - Scherneck, Stephan
AU - Vogel, Heike
AU - Kluge, Reinhart
AU - Wiedmer, Petra
AU - Joost, Hans Georg
AU - Schürmann, Annette
PY - 2011/12
Y1 - 2011/12
N2 - 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, formedium-andshort-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.
AB - 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, formedium-andshort-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.
UR - http://www.scopus.com/inward/record.url?scp=82355165095&partnerID=8YFLogxK
U2 - 10.1210/en.2011-1547
DO - 10.1210/en.2011-1547
M3 - Article
C2 - 21990309
AN - SCOPUS:82355165095
SN - 0013-7227
VL - 152
SP - 4641
EP - 4651
JO - Endocrinology
JF - Endocrinology
IS - 12
ER -