Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet-induced obesity in mice

Brown adipose tissue (BAT) is a thermogenic organ that dissipates stored energy as heat to maintain body temperature in infants and small mammals. This process may also provide protection from development of diet-induced obesity. We found that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, while potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibited reduced expression of BAT-related genes in peripheral white adipose tissue and accumulated significantly more fat than wild-type controls when fed a high fat diet. Our results indicate that ATX and its product LPA are physiologically relevant negative regulators of brown fat adipogenesis and suggest that a decrease in peripheral brown adipose tissue results in increased susceptibility to diet-induced obesity in mice.

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Federico L, Ren H, Mueller PA, Wu T, Liu S, Popovic J, Blalock EM, Sunkara M, Ovaa H, Albers HM, Mills GB, Morris AJ, Smyth SS