Blockade of the Activin Receptor IIB Activates Functional Brown Adipogenesis and Thermogenesis by Inducing Mitochondrial Oxidative Metabolism

Abstract

e Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.

The adipocyte clock controls brown adipogenesis via TGF-β/BMP signaling pathway

“…Together with reciprocally altered BMP activity, these developmental signaling mechanisms driven by Bmal1 modulate brown adipogenesis and consequently affect adaptive thermogenesis in vivo. As crucial negative and positive signals involved in brown adipogenesis, respectively (Fournier et al, 2012;Koncarevic et al, 2012;Kuo et al, 2014;Qian et al, 2013;Tseng et al, 2008;Yadav et al, 2011), our finding of circadian regulation of TGF-b and BMP activities implicates a temporal regulatory control of adipocyte lineage commitment and differentiation.…”

“…Although diverse aspects of metabolism are subjected to circadian regulation (Bass and Takahashi, 2010;Green et al, 2008), whether the adipocyteintrinsic timekeeping mechanism participates in brown fat cell development is not known. Our study demonstrates that the essential transcription activator of the molecular clock, Bmal1, exerts direct temporal control of the TGF-b pathway, a key inhibitory signal of brown fat formation (Fournier et al, 2012;Koncarevic et al, 2012;Yadav et al, 2011). Together with reciprocally altered BMP activity, these developmental signaling mechanisms driven by Bmal1 modulate brown adipogenesis and consequently affect adaptive thermogenesis in vivo.…”

“…As TGF-b and BMPs are key negative and positive signals controlling brown fat formation, respectively (Fournier et al, 2012;Koncarevic et al, 2012;Tseng et al, 2008;Yadav et al, 2011), we postulated that Bmal1 might alter the activities of these pathways to affect brown adipocyte differentiation. We thus determined TGF-b signaling activities in Bmal1 loss-and gain-of-function cells using the TGF-bresponsive luciferase reporters 36TP-Luc (Wrana et al, 1992) and SBE4-Luc (Zhou et al, 1998).…”

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

“…Furthermore, on the basis of recent findings, blockade of activin type II receptors via an antibody approach may also represent a novel therapeutic modality to aid in switching the metabolic balance between adiposity and muscularity, since an increase in skeletal muscle mass via inhibition of the myostatin pathway was accompanied by a decrease in white adipose tissue in mice on a normal or high-fat diet (55). One recently identified mechanism helping to explain this effect is that an ActRIIB antibody has been shown to induce a functional increase in brown fat (56), resulting in enhanced heat production by actually increasing the lipid content in the brown fat tissue (56). Therefore, the potential metabolic benefit of an anti-ActRII antibody approach may relate to a combined increase of functional lean body mass and brown fat.…”

Myostatin: genetic variants, therapy and gene doping

“…An interesting study demonstrated that pharmacological inhibition of AC-TRIIB induced an increase in brown adipose tissue (BAT) through a fine-tuning mechanism that involves activation of myoglobin expression and PGC-1α in BAT. In addition, MSTN inhibition enhances mitochondrial function and uncoupled respiration, thereby increasing energy expenditure (Fournier et al, 2012). Another study found that suppressed ACTRIIB can treat diet-induced obesity and induce a brown fat-like thermogenic gene program in white adipose tissue (Koncarevic et al, 2012).…”