Editors' ChoiceEnergy Metabolism

ARRESTINg Obesity

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Science Translational Medicine  19 Oct 2011:
Vol. 3, Issue 105, pp. 105ec168
DOI: 10.1126/scitranslmed.3003303

Unfair as it might seem, men tend to lose weight more easily than do women. But male or female, a balance of energy intake and energy expenditure defines an individual’s body mass. For weight loss, a simple reduction in energy intake is often confounded by the body’s efficiency in reducing energy expenditure—which is one reason why people find it progressively harder to lose weight while dieting. Most current therapies target energy intake, and few options, other than exercise, increase energy expenditure. Now, Patwari et al. have identified the arrestin domain-containing 3 (ARRDC3) protein—a previously unidentified α-arrestin—as a target with promise for increasing energy expenditure and preventing obesity.

Starting with a genome-wide linkage study, the authors identified a risk locus that was highly associated with obesity in men but not in women. Comparative mapping of the human locus to mouse quantitative trait loci (QTL) linked to fat mass revealed a single candidate gene, ARRDC3, within the risk locus. In mice (Arrdc3) and humans (ARRDC3), the genes are most highly expressed in adipose tissue and are up-regulated by fasting, two features that are consistent with a role in metabolic regulation.

To establish a causal role for ARRDC3 in promoting obesity, Patwari et al. generated mice in which Arrdc3 was knocked out. Loss of Arrdc3 conferred resistance to age-induced obesity and decreased body-fat percentage in both genders, with a more pronounced effect in males. The Arrdc3-deficient mice showed no significant differences in food intake but demonstrated increased energy expenditure, relative to wild-type animals, through both increased metabolic activity and increased activation of thermogenesis—heat production—within adipose tissue. Increased catecholamine signaling through β-adrenergic receptors in fat largely drives adaptive enhancement of thermogenesis. Because other arrestin-related proteins have been shown to regulate receptor turnover and endocytosis, the authors hypothesized that loss of Arrdc3 could lead to enhanced energy expenditure through increased intracellular β-adrenergic signaling. Indeed, coimmunoprecipitation experiments detected a robust interaction between ARRDC3 and the β2- or β3- adrenergic receptors in cotransfected human cells. Moreover, stimulation of mouse adipose tissue explants with catecholamines elicited a greater increase in β-adrenergic signaling from Arrdc3-deficient adipose tissue than in wild-type.

Through complementary studies in humans and mice, Patwari and colleagues have identified ARRDC3 as a regulator of obesity and energy expenditure that acts in part via regulation of β-adrenergic–stimulated thermogenesis. These studies suggest a new avenue of therapy that enhances energy expenditure through inhibition of ARRDC3. Further investigation into the molecular mechanisms of ARRDC3 function in adipose tissue will be critical to the development of new therapies for thwarting obesity. Such agents would be welcome in the campaign against obesity and its related diseases—even if the drugs end up working a bit better in men than in women.

P. Patwari et al., The arrestin domain-containing 3 protein regulates body mass and energy expenditure. Cell Metab. 6 October 2011 (10.1016/j.cmet.2011.08.011). [Abstract]

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