Adipose ABHD6 regulates tolerance to cold and thermogenic programs

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 β 3 -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.

Assessing the Role of Ancestral Fragments and Selection Signatures by Whole-Genome Scanning in Dehong Humped Cattle at the China–Myanmar Border

“…It is worth noting that 82 genes were detected among the four methods mentioned above, indicating that these genes were strongly selected in Dehong humped cattle ( Supplementary Tables S9–S11 ). The annotations of candidate genes revealed the functions that may be associated with heat tolerance ( FILIP1L and ABHD6 ) [ 37 , 38 ]. Interestingly, ABHD6 enables acylglycerol lipase activity, which is a negative modulator of adaptive thermogenesis [ 38 ].…”

“…The annotations of candidate genes revealed the functions that may be associated with heat tolerance ( FILIP1L and ABHD6 ) [ 37 , 38 ]. Interestingly, ABHD6 enables acylglycerol lipase activity, which is a negative modulator of adaptive thermogenesis [ 38 ]. Moreover, Tajima’s D and haplotype patterns were used to further validate the selection of the ABHD6 gene in Dehong humped cattle ( Figure 4 B,C).…”

Alpha/Beta-Hydrolase Domain-Containing 6: Signaling and Function in the Central Nervous System

“…For example, Fisette et al reported that mice lacking ABHD6 in neurons of the ventromedial hypothalamus (VMH) with higher VMH 2-AG levels under conditions of eCB recruitment were physiologically unable to adapt to critical metabolic challenges, suggesting that ABHD6 in the VMH is very important for flexible regulation of energy metabolism ( Fisette et al, 2016 ). Additionally, some studies have shown that ABHD6 is a negative regulator of WAT thermogenesis ( Poursharifi et al, 2020 ). These studies implicate the important role of ABHD6 in the regulation of energy homeostasis by modulating brain circuits.…”

“…α/β-Hydrolase domain-containing 6 (ABHD6) is an integral membrane protein with recently discovered serine hydrolase activity that is, mainly expressed in immune cell-enriched tissues and the CNS( Poursharifi et al, 2017 ). The hydrolytic substrates of ABHD6 are mainly monoacylglycerols (MAGs) ( Poursharifi et al, 2020 ), such as endogenous cannabinoid 2-arachidonoylglycerol (2-AG) and arachidonic acid ( Noguchi et al, 2021 ), which are precursors of prostaglandins and other inflammatory mediators ( Ghosh et al, 2020 ; Larsson et al, 2021 ; Trostchansky et al, 2021 ). As the main hydrolase of postsynaptic eCBs, ABHD6 is involved in regulating neuronal ECS function ( Cao et al, 2019 ).…”

A glycerol shunt functions as a glucose excess security valve in pancreatic β-cells

“…Pancreatic -cells secrete insulin primarily in response to increasing blood glucose levels, through the production of metabolic coupling factors (MCF) that promote insulin granule exocytosis. Disturbed glucose and lipid metabolism, including the glycerolipid/ free fatty acid (GL/FFA) cycle [3][4][5], which is implicated in the regulation of insulin secretion and energy homeostasis [6][7][8], contribute to the pathogenesis of obesity and T2D. The GL/FFA cycle, known to produce several MCF, in particular monoacylglycerol [9], consists of two arms: lipogenesis implicated in the synthesis of glycerolipids, and lipolysis during which glycerolipids, in particular triglycerides (TG) are hydrolyzed to FFA and glycerol [4,5].…”