Abstract
Obesity is associated with blunted β-adrenoreceptor (β-AR)-mediated lipolysis and lipid oxidation in adipose tissue, but the mechanisms linking nutrient overload to catecholamine resistance are poorly understood. We report that targeted disruption of TGF-β superfamily receptor ALK7 alleviates diet-induced catecholamine resistance in adipose tissue, thereby reducing obesity in mice. Global and fat-specific Alk7 knock-out enhanced adipose β-AR expression, β-adrenergic signaling, mitochondrial biogenesis, lipid oxidation, and lipolysis under a high fat diet, leading to elevated energy expenditure, decreased fat mass, and resistance to diet-induced obesity. Conversely, activation of ALK7 reduced β-AR-mediated signaling and lipolysis cell-autonomously in both mouse and human adipocytes. Acute inhibition of ALK7 in adult mice by a chemical-genetic approach reduced diet-induced weight gain, fat accumulation, and adipocyte size, and enhanced adipocyte lipolysis and β-adrenergic signaling. We propose that ALK7 signaling contributes to diet-induced catecholamine resistance in adipose tissue, and suggest that ALK7 inhibitors may have therapeutic value in human obesity.
Highlights
Agonists of β3-adrenoceptors (β3-AR) are effective anti-obesity agents in rodents due to their ability to stimulate lipolysis and lipid oxidation in adipose tissue (Arch, 2011)
Ap2CRE has been reported to be expressed in adipose tissue macrophages (Lee et al, 2013), Alk7 mRNA expression could only be detected in the adipocyte fraction of adipose tissue but not in the stromal-vascular fraction or in spleen (Figure 1—figure supplement 2A–D)
Expression of Alk7 mRNA was reduced by 60% in the adipose tissue of Alk7fx/fx::Ap2CRE mice, while a 98% reduction was achieved in Alk7fx/−::Ap2CRE mice (Figure 1—figure supplement 3A,B)
Summary
Agonists of β3-adrenoceptors (β3-AR) are effective anti-obesity agents in rodents due to their ability to stimulate lipolysis and lipid oxidation in adipose tissue (Arch, 2011). Alternative strategies to enhance catecholamine sensitivity and β-adrenergic signaling selectively in adipose tissue may be effective in combating obesity, but remain unproven. In both humans and rodents, obesity is associated with blunted β-AR-mediated lipolysis and lipid oxidation in adipose tissue (Reynisdottir et al, 1994; Arner, 1999; Jocken et al, 2008), but the mechanisms linking nutrient overload to catecholamine resistance remain poorly understood. ALK7 is highly expressed in rodent and human adipose tissue (Kang and Reddi, 1996; Andersson et al, 2008; Carlsson et al, 2009; Murakami et al, 2012), as well as in a few other tissues implicated in metabolic regulation, such as
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