GPCR in Adipose Tissue Function—Focus on Lipolysis

Abstract

Adipose tissue can be divided anatomically, histologically, and functionally into two major entities white and brown adipose tissues (WAT and BAT, respectively). WAT is the primary energy depot, storing most of the bioavailable triacylglycerol molecules of the body, whereas BAT is designed for dissipating energy in the form of heat, a process also known as non-shivering thermogenesis as a defense against a cold environment. Importantly, BAT-dependent energy dissipation directly correlates with cardiometabolic health and has been postulated as an intriguing target for anti-obesity therapies. In general, adipose tissue (AT) lipid content is defined by lipid uptake and lipogenesis on one side, and, on the other side, it is defined by the breakdown of lipids and the release of fatty acids by lipolysis. The equilibrium between lipogenesis and lipolysis is important for adipocyte and general metabolic homeostasis. Overloading adipocytes with lipids causes cell stress, leading to the recruitment of immune cells and adipose tissue inflammation, which can affect the whole organism (metaflammation). The most important consequence of energy and lipid overload is obesity and associated pathophysiologies, including insulin resistance, type 2 diabetes, and cardiovascular disease. The fate of lipolysis products (fatty acids and glycerol) largely differs between AT: WAT releases fatty acids into the blood to deliver energy to other tissues (e.g., muscle). Activation of BAT, instead, liberates fatty acids that are used within brown adipocyte mitochondria for thermogenesis. The enzymes involved in lipolysis are tightly regulated by the second messenger cyclic adenosine monophosphate (cAMP), which is activated or inhibited by G protein-coupled receptors (GPCRs) that interact with heterotrimeric G proteins (G proteins). Thus, GPCRs are the upstream regulators of the equilibrium between lipogenesis and lipolysis. Moreover, GPCRs are of special pharmacological interest because about one third of the approved drugs target GPCRs. Here, we will discuss the effects of some of most studied as well as “novel” GPCRs and their ligands. We will review different facets of in vitro, ex vivo, and in vivo studies, obtained with both pharmacological and genetic approaches. Finally, we will report some possible therapeutic strategies to treat obesity employing GPCRs as primary target.