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Partial White Adipose Tissue Lipolysis Inhibition: A Novel Approach to Improve Insulin Sensitivity?

Circulating fatty acids (FAs) have an unclear relationship to insulin sensitivity. During fasting and exercise, FAs from white adipose tissue (WAT) lipolysis are delivered to peripheral tissue to meet energy needs. In obesity, excess circulating FAs are thought to drive the development of insulin resistance. Girousse et al., through a variety of in vivo and in vitro human and mouse studies, probe this relationship between WAT lipolysis to insulin sensitivity. First, using human WAT explants from subjects with a large range of BMIs and also pre- and post-bariatric surgery subjects, decreasing WAT lipolysis rate was associated with improving insulin sensitivity. Next, the authors identified a mouse model (haploinsufficient hormone-sensitive lipase [HSL+/-] mice) with reduced lipolysis rates and unchanged fat mass to explore this relationship. Using this model, HSL+/- mice were found to have unaltered FA levels, but did have diminished FA uptake and storage in peripheral tissue. Importantly, HSL+/- mice had improved insulin tolerance and glucose metabolism during high-fat diets, where WAT, skeletal muscle, and liver in the HSL+/- mice each had evidence of improved insulin/glucose tolerance. Probing this question by a different approach, high-fat diet–fed mice were treated for 7 days with an HSL inhibitor, resulting in improved insulin tolerance without a change in fat mass. Confirming these findings in a human model, studies using human adipocytes with HSL knockdown had decreased FA oxidation rates in conjunction with elevated insulin–stimulated glucose uptake. Taken together, these compelling data raise the question of whether partial inhibition of WAT lipolysis can be a strategy to improve insulin sensitivity. — Brian T. Layden, MD, PhD

Girousse et al. …

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  1. doi: 10.2337/db13-dd07 Diabetes vol. 62 no. 7 2625-2626
  1. Free via Open Access: OA