The adipocyte supersystem of insulin and cAMP signaling

White adipose tissue lipid storage is promoted by insulin and antagonized by catecholamines that elevate cAMP to stimulate lipolysis and thermogenic adipocytes. Despite these antagonisms, whole body glucose tolerance is similarly enhanced by both insulin and chronic catecholamine stimulation of adipocytes. We explore the concept that unanticipated convergences of the insulin and cAMP signaling networks in adipocytes contribute to common systemic outcomes. Indeed, the genes Lpin1, Ppargc1a, Gpr35, and Pck1, all known to promote metabolic health, appear to be similarly regulated by both signaling pathways in adipocytes. Additionally, common signaling nodes for these hormones within adipocytes have recently been revealed, including mechanistic target of rapamycin complex (mTORC1), ATP citrate lyase (ACLY), and carbohydrate-responsive element-binding protein (ChREBP). Common stimulatory actions of insulin and cAMP in adipocytes also include glucose transport, glycogen synthesis, de novo lipogenesis, and secretion of adiponectin which enhances glucose tolerance. How such common elements of adipocyte regulation are able to modulate other tissues such as liver and skeletal muscle that control whole body glucose and lipid homeostasis continues to be a key question in the field. Adipose tissue signals to brain, liver, and muscles to control whole body metabolism through secreted lipid and protein factors as well as neurotransmission, but the mechanisms involved are incompletely understood. Adipocytes sequester triglyceride (TG) in fed conditions stimulated by insulin, while in fasting catecholamines trigger TG hydrolysis, releasing glycerol and fatty acids (FAs). These antagonistic hormone actions result in part from insulin’s ability to inhibit cAMP levels generated through such G-protein-coupled receptors as catecholamine-activated β-adrenergic receptors. Consistent with these antagonistic signaling modes, acute actions of catecholamines cause insulin resistance. Yet, paradoxically, chronically activating adipocytes by catecholamines cause increased glucose tolerance, as does insulin. Recent results have helped to unravel this conundrum by revealing enhanced complexities of these hormones’ signaling networks, including identification of unexpected common signaling nodes between these canonically antagonistic hormones. Adipose tissue signals to brain, liver, and muscles to control whole body metabolism through secreted lipid and protein factors as well as neurotransmission, but the mechanisms involved are incompletely understood. Adipocytes sequester triglyceride (TG) in fed conditions stimulated by insulin, while in fasting catecholamines trigger TG hydrolysis, releasing glycerol and fatty acids (FAs). These antagonistic hormone actions result in part from insulin’s ability to inhibit cAMP levels generated through such G-protein-coupled receptors as catecholamine-activated β-adrenergic receptors. Consistent with these antagonistic signaling modes, acute actions of catecholamines cause insulin resistance. Yet, paradoxically, chronically activating adipocytes by catecholamines cause increased glucose tolerance, as does insulin. Recent results have helped to unravel this conundrum by revealing enhanced complexities of these hormones’ signaling networks, including identification of unexpected common signaling nodes between these canonically antagonistic hormones. a type I receptor for the TGFβ family of signaling molecules. In adipocytes, activation of ALK7 reduces β-adrenergic receptor-mediated signaling and lipolysis. an enzyme that catalyzes hydrolysis of triacylglycerols to diacylglycerol and FA. an enzyme that initiates the de novo lipogenesis pathway by converting citrate to acetyl-CoA. a transcriptional regulator that modulates the transcription of genes with cAMP responsive elements in their promoters. glycolytic metabolite activated transcription factors (ChREBPα and ChREBPβ) that regulate glycolytic and lipogenic pathways. hormones that are produced in nerve tissues and adrenal glands and function as neurotransmitters. a standard control diet for rodents, generally providing only 7–12% of the total energy from fat. a G-protein-coupled receptor-triggered signaling cascade in cell communication, which plays a central role in lipolysis and thermogenesis in adipocytes. a pathway that converts carbons from nutrients into FAs, which are precursors for synthesizing TGs or other lipids. an enzyme to convert thyroid hormone from thyroxine (T4) to active form triiodothyronine (T3). the last enzyme in DNL, catalyzing synthesis of palmitic acid. a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. a critical epigenetic modification that changes chromatin architecture and regulates gene expression by modulating chromatin structure. a rate-limiting enzyme, hydrolyzing diacylglycerol to monoacylglycerol and FAs. syndromes with abnormal distribution of fat due to the loss of functional adipose tissue depots. a process which breaks down triacylglycerols to glycerol and free FAs. a protein complex that functions as a nutrient/energy/redox sensor and controls protein and lipid synthesis. a rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. enzymes that catalyze degradation of cyclic nucleotides cAMP and cGMP to AMP and GMP, respectively, reducing cAMP and cGMP signaling. a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). a group of three insulin-activated serine/threonine-specific protein kinases that play key roles in multiple cellular processes. a unique mitochondrial inner-membrane uncoupling protein devoted to heat production (thermogenesis) in beige and brown adipocytes. an inflammatory cytokine produced by macrophages/monocytes during acute inflammation, leading to necrosis or apoptosis.