New research indicates that preventing obesity and diabetes by reducing tissue triglyceride stores might be a good strategy. In the Journal of Clinical Investigation, Chen et al. show that obese mice that lack a key enzyme in the triglyceride synthesis pathway have increased sensitivity to insulin and to leptin, a hormone that enhances energy expenditure.

The enzymes acyl CoA:diacylglycerol acyltransferase 1 and 2 (DGAT1 and -2) catalyse the final step in mammalian triglyceride synthesis. DGAT1 and -2 expression and activity are widely distributed throughout the body, including adipose tissue. Dgat1-deficient, non-obese mice are resistant to diet-induced obesity because of enhanced energy expenditure, which is partly accounted for by an increase in physical activity. DGAT1 deficiency, under normal circumstances, is not associated with a compensatory increase in DGAT2 expression.

The researchers investigated the effect of DGAT1 deficiency on two mouse models of obesity and insulin resistance: agouti yellow and leptin deficient (ob/ob). Agouti yellow mice suffer from severe insulin and leptin resistance. These genetically manipulated mice have increased levels of tissue triglycerides. In agouti yellow mice that lack Dgat1, the deficiency prevents the onset of insulin resistance and protects against obesity. In fact, a reduction in body weight of ∼20% is associated with a dramatic 80% reduction in insulin resistance. Surprisingly, the Dgat1 deficiency in the ob/ob mice did not affect energy expenditure or glucose metabolism. However, this could be due to a compensatory increase of Dgat2 expression that was seen in these mice.

High tissue triglyceride levels are associated with insulin resistance, so the reduced triglyceride content in the Dgat1-deficient agouti yellow mice might enhance insulin sensitivity. However, although obesity is associated with leptin resistance, until now there was little evidence to indicate that decreasing tissue triglyceride content can increase leptin sensitivity. In addition, the decreased adipocyte size in Dgat1-deficient mice might be important, because adipocytes secrete several proteins that modulate glucose metabolism, such as adiponectin and resistin. Interestingly, there is evidence that diacylglycerol antagonizes insulin signalling. Therefore, a reduction in diacylglycerol levels or its precursors, such as fatty acyl CoA, might enhance insulin signalling.

Pharmacological inhibition of DGAT1 could be an effective therapy for diabetes and obesity. Further support for the strategy of targeting fat synthesis can be seen in mice deficient for the fatty-acid-synthesis enzyme acetyl CoA carboxylase 2 (ACC2), which have similar phenotypes to Dgat1-deficient mice. However, in the long term, will enhancing energy expenditure cause shorter lifespans?