A compendium of G-protein-coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

Abstract

With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand-receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein-coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

Keywords: GPCRs; adipose; cyclic nucleotides; thermogenesis.

Figure 1.. Catecholamine biosynthetic pathway and signaling

Epinephrine and norepinephrine (also called adrenaline and noradrenaline, respectively) are made from the amino acid tyrosine via the catecholamine biosynthetic pathway. Epinephrine and norepinephrine signal through nine GPCRs called the adrenoceptors. The α₁ receptors are Gα_q-coupled, α₂ receptors are Gα_i-coupled, and the β-receptors are Gα_s-coupled. The α-receptors are activated by epinephrine and norepinephrine, with epinepherine having a lower potency than norepinephrine on the α₂ receptors. For the β-receptors, in β₁ norepinephrine is more potent than epinephrine, in β₂ epinephrine is more potent than norepinephrine, and in β₃ epinephrine and norepinephrine have similar potencies (adrenoceptors in the IUPHAR/BPS Guide to Pharmacology Database. Available from: https://doi.org/10.2218/gtopdb/F4/2019.4).

Figure 2.. Sympathetic activation of adipocyte lipolysis and thermogenesis

Canonical activation of adipocyte lipolysis and thermogenesis occurs via the sympathetic nervous system. Sympathetic neurons release norepinephrine which activate β-adrenergic receptors on the adipocytes. Activation of these receptors turn on their associated G-proteins by causing the Gβγ (not shown) and Gα_s subunits to dissociate. The Gα_s subunit in turn augments adenylyl cyclase activity. The cAMP produced by adenylyl cyclase causes the regulatory subunits of PKA to dissociate from the catalytic subunits thereby liberating its activity. PKA phosphorylates and activates Hormone Sensitive Lipase (HSL) and other components of the lipolytic pathway. PKA also phosphorylates and activates p38 MAPK that leads to increased Ucp1 transcription and the expression of other pro-thermogenic genes.

Figure 3.. Prostaglandin biosynthetic pathway and signaling

Prostaglandins are oxidative metabolites of arachidonic acid that are produced by cyclooxygenase (COX) enzymes. Arachidonic acid is liberated from the plasma membrane by phospholipase A₂ (PLA₂). COX converts arachidonic acid into the short lived PGH₂ (not shown) which is converted into five primary bioactive prostanoids: PGE₂, PGD₂, PGF_2α, PGI₂ (prostacyclin) and TXA₂ (thromboxane). These prostanoids act locally in an autocrine or paracrine manner. The local action of prostaglandins depends on activation of a family of GPCRs designated EP (for E prostanoid), DP, FP, IP and TP receptors, for the other prostaglandins, respectively.

Figure 4.. Prostaglandin thermogenic signaling

PGE₂−EP3 signaling is well known to be an important regulator of the increased thermogenesis that occurs during fever. In addition, recent studies have shown that prostaglandins are important regulators of adipocyte browning.

Figure 5.. Guanylyl cyclase dependent activation of adipocyte lipolysis and thermogenesis

Activation of both soluble and membrane bound guanylyl cyclases in adipocytes increases intracellular cGMP concentrations. This leads to increased PKG activity, which phosphorylates and activates signaling pathways that cause increased lipolysis and thermogenic gene expression.

Figure 6.. G-protein coupled receptors and cyclic nucleotide regulation of adipose tissue lipolysis and energy expenditure

Many hormones utilize GPCR-cAMP- or GC-cGMP-mediated pathways to regulate adipocyte lipolysis and energy expenditure. These pathways are inherently intertwined as the liberation of fatty acids by lipolysis supplies the fuel for the thermogenesis. It is interesting to note that so many of these hormones utilize the same downstream signaling mechanism. For this reason, treatment of adipocytes with these hormones produces (at least superficially) similar results.