Abstract
Enhanced energy expenditure in brown (BAT) and white adipose tissues (WAT) can be therapeutic against metabolic diseases. We examined the thermogenic role of adipose α/β-hydrolase domain 6 (ABHD6), which hydrolyzes monoacylglycerol (MAG), by employing adipose-specific ABHD6-KO mice. Control and KO mice showed similar phenotypes at room temperature and thermoneutral conditions. However, KO mice were resistant to hypothermia, which can be accounted for by the simultaneously increased lipolysis and lipogenesis of the thermogenic glycerolipid/free fatty acid (GL/FFA) cycle in visceral fat, despite unaltered uncoupling protein 1 expression. Upon cold stress, nuclear 2-MAG levels increased in visceral WAT of the KO mice. Evidence is provided that 2-MAG causes activation of PPARα in white adipocytes, leading to elevated expression and activity of GL/FFA cycle enzymes. In the ABHD6-ablated BAT, glucose and oxidative metabolism were elevated upon cold induction, without changes in GL/FFA cycle and lipid turnover. Moreover, response to in vivo β3-adrenergic stimulation was comparable between KO and control mice. Our data reveal a MAG/PPARα/GL/FFA cycling metabolic signaling network in visceral adipose tissue, which contributes to cold tolerance, and that adipose ABHD6 is a negative modulator of adaptive thermogenesis.
Highlights
Cold endurance and survival of endotherms depends on endogenous heat production mechanisms involving involuntary muscle contractions, or shivering, and nonshivering thermogenesis to maintain a constant core body temperature [1]
The data show that ABHD6 substantially contributed to overall lipolysis (MAG hydrolysis) in 3T3-L1 and primary gonadal adipocytes and suggest a depot-specific role for ABHD6 because it does not contribute to subcutaneous white adipose tissue (WAT) lipolysis
Because deletion of adipose ABHD6, which besides monoacylglycerol lipase (MAGL) catalyzes the last step of the lipolysis arm of the glycerolipid/free fatty acid (GL/FFA) cycle, led to higher energy expenditure and better cold tolerance, we examined the thermogenesis-regulatory role of ABHD6 and how it is related to the GL/FFA cycle in WAT and/or brown adipose tissue (BAT)
Summary
Cold endurance and survival of endotherms depends on endogenous heat production mechanisms involving involuntary muscle contractions, or shivering, and nonshivering thermogenesis to maintain a constant core body temperature [1]. White adipose tissue (WAT) is considered a key energy reservoir, whereas brown adipose tissue (BAT) contributes to adaptive thermogenesis and body temperature control by dissipating energy [2]. Accumulating evidence suggests the existence of alternative thermogenic mechanisms in WAT that do not require UCP1, via ATP-consuming fuel mobilization processes, mitochondrial dynamics, and more [5,6,7,8,9,10]. WAT has a remarkable capacity to respond to thermogenic stimulations by remodeling into beige adipocytes, possibly contributing to adaptive thermogenesis [14]. Considering the large size of WAT depots in the body compared with the BAT, WAT independently of the beiging process may serve as an important tissue for thermogenesis and tolerance to cold. Much remains to be learned about the pathways and key players implicated in WAT under cold stress
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