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.

INTRODUCTION

Glucose is the primary source of energy used by most cells of the body, underscoring the importance of maintaining finely tuned regulation of blood glucose levels for human health. Disruption of any aspect of glucose homeostasis can lead to various pathological outcomes, including the development of obesity and type 2 diabetes mellitus (T2D) (1). T2D is the major form of human diabetes, accounting for ∼90–95% of diagnosed diabetes cases in the United States and affecting 34.2 million people, or ∼10.5% of the US population. Diabetes management is estimated to cost more than $327 billion annually, accounting for 1 in 4 dollars spent on healthcare in the United States (2). T2D, a component of cardiometabolic diseases, is closely associated with a number of comorbidities, including hypertension, obesity, high cholesterol, and nonalcoholic fatty liver disease (3–5). Interestingly, epidemiological studies have shown that ∼86% of patients with T2D are also overweight or obese, suggesting obesity as a major modifiable risk factor for T2D (6). As rates of T2D cases continue to rise, it becomes increasingly important to advance our understanding of the mechanisms and pathways that regulate the development of diabetes and identify novel treatment paradigms. In this article, we review the general concept of peripheral glucose homeostasis and insulin resistance. We then focus on recent advances in our understanding of the hypothalamus as a key regulatory site in glucose regulation, as well as the emerging role of the renin-angiotensin system (RAS), specifically the brain RAS, in obesity and T2D.

PERIPHERAL GLUCOSE HOMEOSTASIS AND INSULIN RESISTANCE

In healthy humans, the maintenance of normal plasma glucose levels reflects the balance between cellular glucose uptake and endogenous glucose production. Elevated plasma glucose is sensed by glucose transporter 2 (GLUT2) in β-cells of the pancreas, leading to an increase in the catabolism of internalized glucose that results in an increase in the ATP/ADP ratio (7). This increased intracellular ATP leads to the closing of ATP-sensitive K⁺ channels (K_ATP), which causes membrane depolarization and increases Ca²⁺ influx by opening voltage-dependent Ca²⁺ channels (7). Cyclic AMP (cAMP) activity and inositol triphosphate (IP₃) signaling also contribute to the mobilization of Ca²⁺ from intracellular stores. The consequent increase in intracellular Ca²⁺ concentration triggers exocytosis of insulin-containing granules, resulting in the secretion of insulin into the extracellular space and, ultimately, into the circulation (Fig. 1A) (7–9). Secreted insulin binds the insulin receptor in various tissues, increasing glucose uptake and utilization. In skeletal muscle, the primary site of insulin-stimulated glucose uptake, binding of insulin to the insulin receptor results in phosphorylation of insulin receptor substrate 1 (IRS1) and increased translocation of glucose transporter 4 (GLUT4) to the cell membrane (10); in addition, it elevates glycogen synthesis through protein kinase B (AKT) signaling (11, 12) (Fig. 1B). Insulin similarly stimulates translocation of GLUT4 to the membrane and promotes glucose uptake in adipose tissue (10, 11). Insulin also stimulates the synthesis of triglycerides and suppresses their hydrolysis, while stimulating free fatty acid (FFA) uptake, resulting in decreased plasma triglyceride levels and adipocyte differentiation (13–15). Activation of hepatic insulin receptor signaling promotes GLUT2 translocation and glycogen synthesis and reduces hepatic glucose production from pyruvate (gluconeogenesis) via IRS phosphorylation and AKT signaling, resulting in elevated glucose uptake and storage and reduced glucose production (16–19) (Fig. 1C). Gluconeogenesis in the liver is also stimulated by high levels of acetyl coenzyme A (acetyl CoA) produced by β-oxidation of fatty acids in the liver and is inhibited by hyperglycemia and high concentrations of ADP. Gluconeogenesis is dependent on a number of enzymes, including phosphoenolpyruvate carboxykinase (PEPCK), hexokinase, and glucose-6-phosphatase (G6Pase). The expression levels and function of these enzymes regulate rates of hepatic glucose production (16–19). Glucose levels and insulin signaling in the liver transcriptionally downregulate the intracellular expression of PEPCK and G6Pase, leading to a reduction in gluconeogenesis, highlighting a feedback loop that maintains plasma glucose levels (20–25). In addition to gluconeogenesis from pyruvate, the liver mobilizes glucose stores via the breakdown of glycogen (glycogenolysis), a process inhibited by high blood glucose levels (16). Effective insulin signaling orchestrates the actions of these critical peripheral organs in concert to maintain blood glucose homeostasis.

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.

T2D, characterized by the inability to effectively regulate blood glucose levels, is often associated with dysfunction in feedback loops between insulin production and insulin action, a phenomenon known as insulin resistance (26). Insulin resistance is a metabolic condition in which a deficiency in insulin signaling leads to the impaired ability of insulin to regulate glucose metabolism in target tissues, mainly skeletal muscle, liver, and adipose tissue (27, 28). As shown in Fig. 1, in the setting of insulin resistance, skeletal muscle and adipose tissue exhibit reduced glucose transporter translocation into the plasma membrane, liver and adipose tissue experience inflammation and disorders in lipid metabolism, and the liver shows increased gluconeogenesis (26, 29). These impaired tissue responses to insulin reduce glucose uptake, elevate plasma FFA and triglyceride levels, and increase hepatic glucose production, resulting in chronic hyperglycemia. Another major deficiency that contributes to the progressive development of T2D, especially in later stages, is impaired functionality of insulin-producing pancreatic β-cells. Conditions that cause insulin resistance, such as hyperlipidemia and obesity, can also lead to β-cell dysfunction (26). For example, increased circulating FFAs and elevated plasma glucose concentrations cause endoplasmic reticulum (ER) stress and oxidative stress, resulting in an apoptotic response, cell damage, and death. In addition, prolonged hyperglycemia increases reactive oxygen species (ROS) production through increased synthesis of misfolded proinsulin and islet amyloid polypeptides; this further drives the proapoptotic response, islet inflammation, and hypertrophy (30, 31) and results in a net loss of β-cells and the development of T2D (26).

THE HYPOTHALAMUS: A KEY REGULATORY SITE IN GLUCOSE HOMEOSTASIS

In addition to the peripheral mechanisms that regulate glucose homeostasis, described earlier, the brain, particularly the hypothalamus, plays an important role in the regulation of blood glucose. This was established as early as 1854, when Dr. Claude Bernard demonstrated that ablation of the floor of the fourth ventricle caused the development of glycosuria in rabbits (32). Accumulating evidence in recent decades suggests that disruption of glucose-sensing mechanisms in the hypothalamus is intimately involved in the pathogenesis of obesity and T2D (33, 34). The hypothalamus plays a critical role in maintaining glucose homeostasis by regulating the pancreatic release of insulin and glucagon through its control over both branches of the autonomic nervous system (35). The sympathetic nervous system stimulates the release of the hormone epinephrine from the adrenal glands. Epinephrine, in turn, stimulates the pancreas to release glucagon, which stimulates the release of stored glucose from the liver, leading to increased blood glucose levels (36–38). On the other hand, the hypothalamus, acting through the parasympathetic nervous system, stimulates the release of insulin from the pancreas. The resulting increase in insulin functions to lower blood glucose levels by promoting the uptake of glucose by cells and tissues throughout the body, including skeletal muscle, liver, and adipose tissue (36, 39–41). The hypothalamus also indirectly regulates the pancreas through the release of growth hormone-releasing hormone (GHRH), which stimulates the release of insulin, and somatostatin, which inhibits the release of glucagon (42–44). Recent research has demonstrated that circulating signaling factors, including glucose, insulin, and leptin, can regulate many hypothalamic neuronal populations to exert significant effects on the regulation of blood glucose, food intake, energy expenditure, and adiposity in both genetically predisposed and diet-induced T2D in animal models (45–48).

Here, we review the neuronal populations and mechanisms of action of several key hypothalamic brain regions involved in glucose regulation, namely, the arcuate nucleus of hypothalamus (ARC), the paraventricular nucleus of hypothalamus (PVN), the ventromedial hypothalamus (VMN), and lateral hypothalamic area (LHA), as illustrated in Fig. 2.

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.

The ARC in Glucose Regulation

The ARC is perhaps the best characterized of the hypothalamic regulatory nuclei involved in the regulation of energy homeostasis. The ARC receives signals from the periphery via the circulation in the form of glucose, insulin, leptin, and other nutrients, and projects to other hypothalamic nuclei, including the PVN and VMN, to regulate autonomic function and glucose metabolism. The ARC contains two main neuronal populations: 1) orexigenic agouti-related peptide (AgRP)- and neuropeptide Y (NPY)-expressing neurons and 2) anorexigenic proopiomelanocortin (POMC) neurons (49–51). AgRP/NPY and POMC neurons play opposite roles in glucose regulation. Under conditions of negative energy balance or decreased circulating glucose, AgRP/NPY neurons are activated, inducing an orexigenic effect that promotes food intake and insulin resistance. On the other hand, under conditions of positive energy balance or increased circulating glucose, POMC neurons are activated, resulting in an anorexigenic effect that inhibits food intake and improves hepatic insulin sensitivity (34, 51, 52). Chhabra et al. (53) investigated the role of hypothalamic ARC POMC neurons in glucose homeostasis using a mouse model in which these neurons were specifically deleted, reporting that glycosuria levels are higher in mice lacking ARC POMC neurons, indicating increased renal glucose excretion. These mice also show improved glucose tolerance, despite being obese and insulin resistance. This improved glucose tolerance after deletion of ARC POMC neurons is likely attributable to a reduction in renal sympathetic nerve activity, which plays a critical role in renal glucose reabsorption. These results highlight the crucial role of ARC POMC neurons in maintaining basal renal sympathetic nerve activity and regulating glucose metabolism. Moreover, both AgRP neurons and POMC neurons express insulin receptors, and central administration of insulin to the third ventricle stimulates a reduction in body weight through a decrease in appetite as well as decreased expression of NPY and increased expression of POMC in the ARC (54–56). Electrophysiological studies have shown that insulin induces membrane hyperpolarization and reduces action potential frequency in AgRP neurons, effects that are ablated by the K_ATP channel blocker, tolbutamide (57).

In addition to glucose and insulin signaling, leptin signaling in AgRP/NPY and POMC neurons plays an important role in the regulation of glucose homeostasis. Leptin, known as a satiety hormone, reduces appetite and leads to weight loss when applied centrally (45). A leptin deficiency or certain mutations in the leptin receptor, as exemplified by ob/ob and db/db mice, respectively, results in a dramatic obesity phenotype, underscoring the contributions of the brain to the regulation of energy homeostasis (45). Leptin hyperpolarizes AgRP/NPY gamma aminobutyric acid (GABA)-expressing neurons while depolarizing POMC neurons. AgRP/NPY neurons within the ARC project to POMC neurons, providing a reinforcing mechanism for leptin sensitization of the anorexigenic effect (58). Leptin signaling defects are often implicated in obesity and obesity-associated comorbidities, such as T2D (59). Intracerebroventricular infusion of leptin in rats or ob/ob mice reduces appetite and NPY mRNA levels in the ARC and increases PVN levels of corticotropin-releasing hormone (CRH), which is associated with inhibition of food intake (60, 61). In leptin receptor-deficient rats, restoration of leptin receptors in the ARC has been shown to improve peripheral insulin sensitivity through suppression of hepatic gluconeogenesis via the vagus nerve (62). On the other hand, intracerebroventricular (ICV) administration of leptin or local injection of leptin into the ARC results in an increase in both liver sympathetic nerve activity and parasympathetic nerve activity, assessed by directly recording nerve activity (63). These results highlight the potential significance of leptin in the ARC in regulating glucose homeostasis by modulating hepatic autonomic outflow.

In summary, glucose-, insulin-, and leptin-sensitive neurons act to mediate glucose uptake and insulin sensitivity by exerting opposing effects on neuronal populations, establishing the ARC as a critical nucleus in the central regulation of glucose homeostasis.

The PVN in Glucose Regulation

The PVN is a hypothalamic hormonal and autonomic control center adjacent to the third ventricle that receives inputs from many other regulatory nuclei, such as the ARC, lateral hypothalamic area, and subfornical organ, and projects to hindbrain autonomic control centers, including the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMV), and area postrema (AP), as well as the posterior pituitary (64–66). Previously viewed as a throughput center for neuronal signaling, the PVN is now known to be an important site of signal integration in the autonomic regulation of glucose homeostasis (65, 66). It receives projections from AgRP/NPY and POMC neurons in the ARC, inputs that have been strongly implicated in the regulation of glucose homeostasis (67, 68). Excitation of ARC NPY-expressing neurons has been shown to regulate brown adipose tissue (BAT) thermogenesis and sympathetic outflow, which contribute to energy balance through NPY signaling to tyrosine hydroxylase (TH)-expressing neurons in the PVN (67). Moreover, retrograde labeling from interscapular BAT results in labeling of PVN neurons, showcasing the existence of PVN-BAT pathways and implicating the PVN in the modulation of energy homeostasis (69, 70). The PVN also receives inputs from the suprachiasmatic nucleus (SCN), such that SCN neurons project onto both presympathetic and preparasympathetic PVN neurons that innervate the liver (71). In rats, activation of sympathetic preautonomic neurons in the PVN, either by inhibition of GABA receptors or stimulation of N-methyl-d-aspartate (NMDA) receptors, results in a significant elevation in blood glucose level, further indicating the importance of the PVN as a site of signal integration for regulation of glucose homeostasis (72).

The PVN is a heterogeneous nucleus that contains multiple neuronal populations (64, 73, 74). Some neuronal populations that influence glucose regulation in the PVN have been previously investigated (65, 68, 74, 75). Melanocortin 4 receptor (MC4R)-expressing neurons in the PVN have been identified as key to the regulation of blood glucose levels. A recent neuroanatomical study showed that MC4R-expressing PVN neurons project to many brain regions that are critical for autonomic and neuroendocrine regulation, such as the median eminence, NTS, ventrolateral medulla, and thoracic spinal cord (76). Hepatic and skeletal muscle insulin sensitivity is improved by application of an MC4R agonist in the PVN and impaired by MC4R antagonists (77). In mice, knockout of MC4R in the PVN results in decreased renal sympathetic nerve activity, circulating adrenaline levels and GLUT2 expression in the kidney, which collectively lead to reduced glucose reabsorption and elevated glucosuria, further suggesting the critical role of hypothalamic MC4Rs in the regulation of glucose homeostasis (78). In addition, the PVN contains CRH neurons that project to autonomic regulatory nuclei in the brainstem (65, 79, 80). These neurons, which mediate an anorexigenic neuroendocrine and autonomic response, are involved in the control of appetite and adiposity, a leptin-dependent process mediated by leptin-induced increases in CRH expression in the PVN (65, 81). ICV infusion of CRH drives elevations in locomotor activity, BAT thermogenesis, and lipolysis, and also reduces food intake and weight gain. CRH activity in the PVN acts to oppose NPY inputs from the ARC and results in increased sympathoexcitation; conversely, the expression of CRH is reduced by fasting, which reinforces satiety-dependent regulation of food intake and energy homeostasis (65).

Glucose-sensing neurons in the hypothalamus are often implicated in the neuroendocrine modulation of blood glucose (82). As previously mentioned, glucose- and insulin-sensitive neurons are also present in the PVN (75). Similar to the case in pancreatic β-cells, closing of K_ATP channels in hypothalamic glucose-excited neurons following glucose metabolism-dependent increases in the ATP/ADP ratio causes many of these neurons to depolarize; notably however, this depolarization is mediated by nonselective cation channels instead of K_ATP channels in glucose-excited, preautonomic PVN neurons (75). Glucose-excited neurons in the PVN control glucagon and insulin secretion via the autonomic nervous system, and both sympathetic and parasympathetic pathways linking the PVN and pancreas have been previously described (83, 84). The PVN also contains glucose-inhibited neurons (75). Glucose-inhibited neurons are activated subsequent to a low glucose concentration, with glucokinase suggested as the critical glucose-sensing enzyme in these neurons through modulation of the ATP/ADP ratio (85, 86). Neuronal overexpression of glucokinase in the PVN results in increased endocrine release of glucagon-like-peptide 1 (GLP1) and improved glucose homeostasis following an oral glucose tolerance test (87). In summary, the PVN serves as an integrative hub for signaling from the circulation and other regulatory nuclei that is critical for the effective regulation of glucose homeostasis.

The VMN and LHA in Glucose Regulation

In addition to the PVN and ARC, the VMN and LHA regions of the hypothalamus are critical for the central regulation of glucose homeostasis. The VMN is a regulatory nucleus adjacent to the PVN and ARC that also contains glucose-excited and glucose-inhibited neurons (85, 88). Early research on neuronal mechanisms of satiety, detailed in an excellent review by King et al. (89), identified the VMN as a potent regulator of body weight and energy metabolism, as evidenced by the fact that lesions to the VMN result in obesity, hyperphagia, and diabetes (89, 90). As is the case for the ARC, the VMN contains abundant leptin-sensitive neurons (91, 92). Lesion of the VMN in rats leads to leptin insensitivity and the development of obesity (89, 93). Leptin signaling in the VMN also regulates the glucose sensitivity of some glucose-excited neurons. Both leptin and insulin open K_ATP channels via the PI3K pathway, which mediates the activation of glucose-excited neurons (94, 95). These glucose-sensing neurons in the VMN, which have been implicated in the detection and correction of hypoglycemia (85, 88, 96), may become hypersensitive to reductions in blood glucose during T2D and thus may contribute to elevations in fasting blood glucose due to an overcompensated corrective response (94). In addition to sensitizing tissues to glucose, VMN neurons regulate the expression of two key enzymes, the gluconeogenic enzyme, PEPCK, and glycolytic enzyme, pyruvate kinase, in the liver through modulation of sympathetic outflow to the liver (97). It has been recognized for some time that VMN neurons are important in thermoregulation through the autonomic control of BAT, although the full contribution of BAT to adult energy metabolism was not recognized until more recently (98, 99). VMN neurons have also been implicated in the control of white adipose tissue (WAT) lipolysis, mainly through the sympathetic nervous system (99). In particular, steroidogenic factor 1 (SF1)-expressing neurons in the VMN have been shown to regulate sympathetic nerve activity and contribute to the regulation of glucose homeostasis (99, 100). Although many of the neuronal pathways from the VMN involved in the regulation of energy metabolism and blood glucose are not yet fully understood, the VMN is nonetheless a key area in the regulation of energy intake and expenditure and glucose homeostasis that, when disrupted, contributes to the development of T2D.

It should be noted that the LHA plays crucial roles in regulating various physiological functions, including feeding behavior, energy balance, circadian rhythm, and glucose homeostasis (101–104). The LHA contains a population of neurons that is sensitive to changes in blood glucose levels (82, 105, 106) such that their activity is inhibited by glucose and increased by insulin or 2-deoxy-d-glucose. Inhibition of these neurons by glucose is thought to play a role in suppressing feeding behavior and stimulating insulin secretion (106–108). The LHA receives inputs from a variety of sources, including the circulation, gut, and brainstem, and thus acts as an integrative neural center that monitors glucose levels (103, 109). It regulates glucose homeostasis by modulating the activity of the autonomic nervous system and the release of hormones such as ghrelin, insulin, and glucagon (82, 110–112). The LHA exerts its function in glucose regulation through projections to various brain regions, including the PVN, ARC, VMH, NTS, and DMV (113–115). It also sends efferent projections directly to sympathetic preganglionic neurons that control the sympathetic innervation of the liver and other organs involved in glucose metabolism (115). Collectively, these observations highlight the LHA as a complex brain region that plays a critical role in the regulation of glucose metabolism.

THE EMERGING ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN OBESITY AND GLUCOSE REGULATION

Introduction to the Systemic RAS and the Brain RAS

In the systemic RAS, prorenin is synthesized and converted to active renin by the proteolytic removal of a 43-amino acid prosegment in juxtaglomerular cells of the kidney (116). Active renin, the rate-limiting enzyme of the RAS, is released into the circulation, where it cleaves angiotensinogen (AGT), secreted by the liver, to angiotensin I (Ang I), which is then converted into angiotensin II (Ang II), the primary effector peptide of the RAS, by angiotensin-converting enzyme (ACE). Ang II binds the angiotensin II type 1 receptor (AT_1aR) to produce a pressor response that elevates blood pressure through increases in fluid retention, sympathetic nerve activity, aldosterone secretion, and vascular constriction. This vasoconstrictive response is countered by a vasodilatory response induced by the binding of Ang-(1–7), a product of the action of angiotensin-converting enzyme 2 (ACE2) on Ang II, to the Mas receptor (MasR), angiotensin II type 2 receptor (AT₂R), or G-protein-coupled receptor MrgD (116–118).

In addition to the canonical RAS, a local tissue RAS is present in various tissues (119). Of particular note in this context is the brain RAS. Although levels of renin in the brain are known to be low, the brain RAS is clearly activated, mostly through the (pro)renin receptor (PRR) (120–123). When bound, prorenin, an endogenous ligand of the PRR, is nonproteolytically activated and cleaves AGT to Ang I, allowing for the production of Ang II. As such, the PRR is a major contributor to the production of Ang II in the brain (123, 124). Increased hypothalamic Ang II is associated with elevated blood pressure through increases in sympathetic nerve activity and increased release of vasopressin via AT_1aR, a G-protein-coupled receptor that engages MAPK, ERK1/2, and JAK/STAT signaling cascades (123, 125). In addition to Ang II-dependent signaling, the PRR also activates Ang II-independent signaling pathways involving MAPK and ERK1/2 signaling cascades, resulting in the upregulation of targets with proinflammatory properties, including NADPH oxidase (NOX) and NF-κB (126–129).

Role of the Systemic RAS in Obesity and Glucose Regulation

The RAS, traditionally viewed as a modulator of blood pressure and cardiovascular function, has emerged as a potential component of metabolic regulation (130–132). Overactivation of circulating and peripheral tissue RAS is associated with metabolic dysfunctions, including obesity and insulin resistance (133, 134), as illustrated in Fig. 3. Elevated RAS activity in peripheral tissues has been reported in both rodent models of obesity and humans with obesity and is thought to be especially relevant in adipose tissues (134, 135). Adipose tissue expresses all components of the RAS, including AGT, prorenin, and ACE2, as well as the receptors of angiotensin peptides, AT_1aR, AT₂R, and MasR, indicating that adipose tissue has the capacity to produce angiotensin peptides and participate in angiotensin signaling pathways (136, 137). In obesity, RAS overactivity in adipocytes results in reduced adipocyte differentiation and increased hypertrophy in addition to elevated secretion of proinflammatory cytokines. Adipose tissue is also a significant contributor to elevated circulating AGT during obesity and displays a feed-forward endocrine effect on RAS activity during the metabolic disease state (138).

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.

Recent studies have implicated the PRR in adipose tissue in energy homeostasis, showing that mice lacking the PRR in adipose tissue show increased locomotor activity, reduced fat mass, and improved insulin sensitivity after being fed a high-fat diet (HFD) (139). These data suggest that the PRR is a critical factor in adipose RAS function in the context of obesity and its related complications, such as T2D. Interestingly, antihypertensive agents that target the RAS, including angiotensin receptor blockers and ACE inhibitors, have been shown to exert an insulin-sensitizing effect (140, 141). In contrast, antihypertensive treatment with β-adrenergic receptor blockers does not cause insulin sensitization, reinforcing the association of RAS activity with insulin resistance and suggesting that RAS activity, independent of changes in blood flow or pressure, drives changes in insulin sensitivity (133).

The Brain RAS in Metabolic Regulation

An increase in brain RAS activity is a pivotal step in the pathogenesis of many cardiovascular diseases, including hypertension and heart failure. It has been established that the brain RAS plays a key role in the central regulation of blood pressure and body fluid homeostasis through modulation of sympathetic activity (121, 122, 127, 142). Individuals with obesity are more likely to develop hypertension, and the increased sympathetic activity observed in obesity is a defining characteristic of neurogenic hypertension (143–145). On another level, the brain RAS has recently emerged as a potential signaling axis in the regulation of metabolic rate (146, 147). Kloet et al. (148) showed that chronic ICV administration of Ang II results in a decrease in body mass and adipose mass while enhancing BAT thermogenesis and WAT lipolysis in Long-Evans rats. Similarly, Porter and Potratz (149) reported that ICV infusion of Ang II decreases food intake and increases energy expenditure in both young and adult rats. Selective deletion of renin-b in the brain increases resting metabolic rate concomitant with elevated sympathetic nerve signaling to BAT (150), whereas deletion of AT_1aR in leptin-expressing cells in the ARC prevents the elevation of resting metabolic rate in response to a high-fat diet (151). These studies suggest the important role of the brain RAS in the control of energy homeostasis. However, the role of the brain RAS in glucose regulation is largely unknown.

Emerging Role of the Brain RAS and PRR in Glucose Regulation

Growing evidence indicates that components of the RAS are locally expressed in several hypothalamic regions involved in the regulation of glucose metabolism. It has been reported that AGT, the precursor of Ang II, is expressed in neurons in the supraoptic nucleus and PVN (152). Immunocytochemical labeling has revealed that Ang II and Ang-(1–7) are localized to the supraoptic nucleus and PVN (153–156). Correa et al. (157) have demonstrated the localization of ACE to several hypothalamic areas, including the supraoptic nucleus, anterior hypothalamic nucleus, periventricular nucleus, and PVN. It has also been shown that AT1_aR is highly expressed in the PVN and in ARC AgRP neurons (151, 158), and immunohistochemical studies have demonstrated the expression of MasR throughout the hypothalamus, with intense immunoreactivity observed in the supraoptic nucleus and PVN (159, 160). Moreover, the PRR is reported to be expressed in the PVN (120) in arginine vasopressin and oxytocin in magnocellular neurons (161, 162), the ARC (163), the NTS, and the rostral ventrolateral medulla (RVLM) (122), key autonomic regulatory brainstem nuclei that receive input from the hypothalamus. These studies provide anatomical insight into how the brain RAS in specific hypothalamic regions may play a role in metabolic disorders, such as T2D.

Interestingly, several clinical studies performed in recent decades have demonstrated that the development of diabetes and its complications in humans is significantly associated with elevated plasma prorenin concentrations (164–169). In contrast, researchers have found that the level of active renin in plasma is within the normal range or lower in most patients with diabetes (165, 170, 171). Some studies have suggested that such increases in plasma prorenin in diabetes might be caused by an impaired ability of the kidney to convert prorenin to active renin (164, 172). Although the kidney is a major source of circulating prorenin, the roles of other nonrenal sources of prorenin cannot be excluded (169, 173, 174). Nevertheless, whether the elevated plasma prorenin level in diabetes is clinically significant remains largely unknown.

The PRR, a key component of the brain RAS (175), mediates the formation of Ang II (122, 175), a major bioactive RAS peptide in the central nervous system (CNS), in response to binding of its ligand, prorenin. Notably, however, this receptor can also signal through Ang II-independent pathways (129, 176–180). In a mouse model of HFD-induced obesity with elevated glycemia, prorenin was reported to be elevated in both the plasma and hypothalamic tissue of the brain (163). These findings provide plausible mechanisms supporting a role for plasma prorenin and shed new light on the potential clinical significance of elevated plasma prorenin in diabetes. Indeed, neuronal PRR deletion protects against the development of obesity-related hypertension by reducing hypothalamic Ang II formation and improving autonomic function (163), findings in line with previously described mechanisms of brain RAS regulation of cardiovascular disease (120). Interestingly, PRR deletion in HFD-fed mice was also shown to reduce glycemia, improve glucose intolerance, and protect against pancreatic islet hypertrophy (163), indicating that neuronal PRR signaling might be critical for the development of HFD-induced T2D. However, the molecular signals, synaptic and neural circuitries, and peripheral glucose-regulating mechanisms involved remain to be determined. A hypothesis illustrating brain RAS-related mechanisms in the regulation of glucose metabolism is presented in Fig. 4.

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.

CONCLUSIONS AND PERSPECTIVES

Central regulatory nuclei of the hypothalamus, including the ARC, VMN, LHA, and PVN play key roles in modulating glucose homeostasis and satiety. These key hypothalamic brain nuclei mediate food intake, energy expenditure (via thermogenesis, gluconeogenesis, production of insulin and glucagon), and insulin sensitivity (via autonomic and neuroendocrine signaling), and their impaired function can result in the development of obesity and T2D. Studies highlighted here demonstrate a robust and important role of the hypothalamus in the regulation of glucose homeostasis. An in-depth understanding of the function, interaction, and identity of neuronal populations that affect metabolic and autonomic responses in integrative regulatory nuclei may be the extra “weight on the scales” needed to balance a Western diet and lifestyle with healthy body weights and outcomes. Untangling the neural circuitry responsible for the central regulation of metabolic dysfunction would be the next step toward targeted therapeutics against metabolic disease.

Overactivation of the brain RAS promotes both hypertension and hyperglycemia, and links multiple comorbidities of cardiometabolic disease. The literature reviewed above describes potential diverse mechanisms involving the brain RAS in the central regulation of blood glucose through autonomic and neuroendocrine influences. Given the shared functions of regulatory nuclei involved in hypertension and glucose regulation, a deeper understanding of the mechanisms involved in the function and modulation of the brain RAS, which is currently lacking, may lead to the identification of therapeutic strategies against elevated blood glucose and metabolic disorders.

GRANTS

This work was supported, in part, by grants from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (R01HL122770, and R35HL155008), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK135621), and NIH/National Institute of General Medicine Science (NIGMS) (1P20GM130459) to Y. Feng Earley.

DISCLAIMERS

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the granting agencies.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Y.F.E. conceived and designed research; S.P., C.J.W., and Y.F.E. prepared figures; S.P. and C.J.W. drafted manuscript; S.P., C.J.W., and Y.F.E. edited and revised manuscript; S.P., C.J.W., and Y.F.E. approved final version of manuscript.