Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control

Abstract

Obesity is commonly associated with sympathetic overdrive, which is one of the major risk factors for the development of cardiovascular diseases, such as hypertension and heart failure. Over the past few decades, there has been a growing understanding of molecular mechanisms underlying obesity development with central origin; however, the relative contribution of these molecular changes to the regulation of cardiovascular function remains vague. A variety of G-protein coupled receptors (GPCRs) and their downstream signaling pathways activated in distinct hypothalamic neurons by different metabolic hormones, neuropeptides and monoamine neurotransmitters are crucial not only for the regulation of appetite and metabolic homeostasis but also for the sympathetic control of cardiovascular function. In this review, we will highlight the main GPCRs and associated hypothalamic nuclei that are important for both metabolic homeostasis and cardiovascular function. The potential downstream molecular mediators of these GPCRs will also be discussed.

Elucidating the role of Rgs2 expression in the PVN for metabolic homeostasis in mice

“…Among many functionally distinct hypothalamic nuclei, the paraventricular nucleus of hypothalamus (PVN) has been considered a key integrative center in the brain for maintaining metabolic homeostasis through its projections to different hypothalamic and brainstem nuclei that regulate energy intake and/or expenditure [ [6] , [7] , [8] ]. A variety of G-protein-coupled receptors (GPCRs) involved in metabolic control are enriched in the PVN [ 9 ], such as melanocortin 4 receptor (MC4R), glucagon-like peptide 1 receptor (GLP1R), and various subtypes of serotonergic and adrenergic receptors, and functional manipulations of different G α subunits within the PVN cause metabolic alterations [ 10 , 11 ], indicating a critical role of PVN GPCR-G α signaling pathways in whole-body energy metabolism. However, the regulatory components of PVN GPCR-G α signaling pathways affecting metabolic homeostasis are not well understood.…”

Leptin signaling and leptin resistance

“…AT1A receptors colocalize with leptin receptors in the AgRP neurons [ 181 ]. Ablation of AT1A receptors specifically in the LepR-expressing neurons diminishes the RMR in response to a high-fat diet or deoxycorticosterone acetate-salt treatments [ 181 , 182 ]. Thus, angiotensin interacts with leptin in the brain to regulate RMR.…”