Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat

Abstract

Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

“…20 Although their clinical and pathological data were given, genetic information is lacking; however, these individuals may harbor mutations in DGAT1. Although Dgat1 deficiency in mice has conferred resistance to dietinduced obesity and increased insulin and leptin sensitivity, 7,8,21 this may well be different in humans. The susceptibility of humans, as compared with other mammals, on DGAT1 deficiency may be due to the expression of DGAT enzymes.…”

“…6 DGAT1 may be a target for antiobesity drugs, based upon studies of a DGAT1-knockout mouse exhibiting resistance to diet-induced obesity, increased energy expenditure, and insulin and leptin sensitivities. 7,8 However, only a single family with DGAT1 mutations has been described. Here we present two additional families with biallelic defects in DGAT1, expanding current knowledge of the spectrum of the disease phenotype and its mutation profile as well as its potential prevalence.…”

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

“…In addition, DGAT knockout mice show elevated energy expenditure and increased activity, suggesting an increase in FA oxidation. 5 Similarly, deletion of acetyl-CoA carboxylase 2 (ACC2), a key enzyme for de novo FA synthesis, leads to a lean mouse showing an increase in FA oxidation. 6 This is due to a fall in malonyl-CoA, the product of the ACC reaction.…”

New isochaetochromin, an inhibitor of triacylglycerol synthesis in mammalian cells, produced by Penicillium sp. FKI-4942: I. Taxonomy, fermentation, isolation and biological properties

“…Several approaches have been evaluated for the treatment of obesity, and two drugs have been approved for use: sibtramine, which acts centrally to inhibit serotonin and noradrenaline uptake, 1,2 and orlistat, which inhibits lipid lipase and therefore interferes with lipid absorption from the small intestine. 3,4 One potential strategy for the treatment of obesity is to block TG synthesis; 5 therefore, inhibitors of TG synthesis are expected to be therapeutic agents for obesity. 6,7 TG is synthesized by a number of enzymes.…”