Non-adrenergic control of lipolysis and thermogenesis in adipose tissues

Abstract

The enormous plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. In energy balance, lipolysis of triacylglycerols and re-esterification of free fatty acids are opposing processes operating in parallel at identical rates, thus allowing a more dynamic transition from anabolism to catabolism, and vice versa. In response to alterations in the state of energy balance, one of the two processes predominates, enabling the efficient mobilization or storage of energy in a negative or positive energy balance, respectively. The release of noradrenaline from the sympathetic nervous system activates lipolysis in a depot-specific manner by initiating the canonical adrenergic receptor-G s -protein-adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A pathway, targeting proteins of the lipolytic machinery associated with the interface of the lipid droplets. In brown and brite adipocytes, lipolysis stimulated by this signaling pathway is a prerequisite for the activation of non-shivering thermogenesis. Free fatty acids released by lipolysis are direct activators of uncoupling protein 1-mediated leak respiration. Thus, pro-and anti-lipolytic mediators are bona fide modulators of thermogenesis in brown and brite adipocytes. In this Review, we discuss adrenergic and non-adrenergic mechanisms controlling lipolysis and thermogenesis and provide a comprehensive overview of pro-and anti-lipolytic mediators.

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

“…Interestingly, the divergent pathways that mediate iWAT beiging, emanating from nerve fibers in cold exposed mice vs macrophages in iAdFASNKO mice, appear to converge at the level of the cAMP/PKA signaling pathway within the iWAT adipocytes. Thus, greatly increased abundance of phospho-perilipin and phosphohormone sensitive lipase, known substrates of PKA 71,72 , are observed in the iWAT of iAdFASNKO mice compared to wild type mice (Extended Data Fig. 1a), similar to what is observed in cold exposed mice 73,74 .…”

Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation

“…SCTR is a G s protein-coupled GPCR (G-protein-coupled receptor) receptor of the class II receptor family (Afroze et al, 2013). Upon secretin binding, SCTR activates lipolysis by cAMP-PKA signaling in murine white adipocytes (Braun et al, 2018). In brown adipocytes, free fatty acids released by lipolysis serve as activators of UCP1 and substrates for thermogenesis.…”

“…Furthermore, gut hormones directly modulate triglyceride metabolism in adipocytes. For example, the gut hormone peptide YY (PYY) inhibits lipolysis via Y2R coupled to G i signaling (Valet et al, 1990), and secretin stimulates lipolysis through the secretin receptor (Sctr) coupled to G s (Braun et al, 2018). As lipolysis is an essential prerequisite of BAT thermogenesis, we therefore set out to identify gut hormones that directly activate meal-associated thermogenesis in BAT and control satiation.…”

The weight of nutrients: kynurenine metabolites in obesity and exercise

“…Thereto, mice treated with a A 2A agonist exhibit increased energy expenditure as well as resilience to the effects of high-fat diet feeding as illustrated by improved glucose tolerance and a leaner phenotype than control mice [51]. In brown and beige adipocytes, lipolysis is central, but not indispensable, for thermogenesis and Ucp1dependent uncoupling [52][53][54][55].…”