The hypothalamus as a key regulator of glucose homeostasis: emerging roles of the brain renin-angiotensin system

Abstract

The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.

Keywords: (pro)renin receptor; central nervous system; glucose; metabolism; type 2 diabetes mellitus.

Graphical abstract

Figure 1.

Simplified schematic showing how hyperglycemia regulates insulin production, glucose uptake, and gluconeogenesis. Elevated glucose levels promote insulin release from pancreatic β-cells into the bloodstream (A). In skeletal muscle and adipose tissue, activation of insulin signaling promotes translocation of GLUT4 to the cell membrane, resulting in increased glucose uptake (B). Insulin binds the insulin receptor (InsR) in the liver and inhibits gluconeogenesis (C). Chronic hyperglycemia stimulates overproduction and release of insulin, together with hyperlipidemia (increased FFA), and induces insulin resistance, resulting in reduced glucose uptake by skeletal muscle and adipose tissue, increased hepatic glucose production, and thus sustained hyperglycemia (D). AKT, protein kinase B; FBPase, fructose-1,6-bisphosphatase; FFA, free fatty acid; FOXO1, forkhead box protein O1; GCK, glucokinase; G6Pase, glucose-6-phosphatase; IRS1, insulin receptor substrate 1; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PFK-1, phosphofructokinase-1; PI3K, phosphoinositide 3-kinase; PK, pyruvate kinase. Created with BioRender.com.

Figure 2.

The cellular identity and mechanisms of action of key hypothalamic brain nuclei in the regulation of blood glucose homeostasis. Schematic illustration of various types of neurons in the hypothalamus, including the paraventricular nucleus of hypothalamus (PVN), ventromedial hypothalamus (VMN), lateral hypothalamic area (LHA), and arcuate nucleus of the hypothalamus (ARC), that regulate glucose homeostasis via the autonomic nervous system. AgRP, agouti-related peptide; CRH, corticotropin-releasing hormone; GABA, γ-aminobutyric acid; GCK, glucokinase; Glu, glutamate; Hcrt, hypocretin/orexin; LepR, leptin receptor; MCH, melanin-concentrating hormone; MC4R, melanocortin 4 receptor; nAchR, nicotinic acetylcholine receptor; NPY, neuropeptide Y; OXT, oxytocin; POMC, proopiomelanocortin; SF1, steroidogenic factor 1; TH, tyrosine hydroxylase. Created with BioRender.com.

Figure 3.

The systemic RAS in blood pressure and glucose regulation. Upregulation of the circulating RAS activates downstream G-protein-coupled receptor signal pathways leading to elevated blood pressure, reduced secretion of insulin from the pancreas, reduced adipocyte differentiation, and impaired insulin sensitivity. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; ANG I, angiotensin I; ANG II, angiotensin II; AT₁R, angiotensin II type 1 receptor; AT₂R, angiotensin II type 2 receptor; GPCR, G-protein-coupled receptor; MrgD, MAS-related G-protein coupled receptor type D. Created with BioRender.com.

Figure 4.

Proposed mechanisms of the brain RAS in glucose regulation. Increased circulating prorenin and/or hypothalamic prorenin, and an imbalance in the bioavailability of angiotensin peptides (Ang II vs. Ang 1–7) results in brain RAS overactivation. This augmented brain RAS activity induces neuroinflammation and alters neuronal activity, leading to autonomic or neuroendocrine dysfunction, and thus abnormal peripheral glucose metabolism. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; ANG I, angiotensin I; ANG II, angiotensin II; ARC, arcuate nucleus of hypothalamus; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; GPCR, G-protein coupled receptor; LHA, lateral hypothalamic area; ME, median eminence; MrgD, MAS-related G-protein coupled receptor type D; NTS, nucleus tractus solitarius; PRR, (pro)renin receptor; PVN, paraventricular nucleus of hypothalamus; RVLM, rostral ventrolateral medulla; VMN, ventromedial hypothalamus. Created with BioRender.com.