The Neural Circuits Underlying Reciprocal Cardio-Metabolic Crosstalk

Abstract

The interplay of various body systems, encompassing those that govern cardiovascular and metabolic functions, has evolved alongside the development of multicellular organisms. This evolutionary process is essential for coordination and maintenance of homeostasis and overall health by facilitating adaptation of the organism to internal and external cues. Disruption of these complex interactions contributes to the development and progression of pathologies that involve multiple organs. Obesity-associated cardiovascular risks, such as hypertension, highlight the significant influence that metabolic processes exert on the cardiovascular system. This cardio-metabolic communication is reciprocal, as indicated by substantial evidence pointing to the ability of the cardiovascular system to affect metabolic processes, with pathophysiological implications in disease conditions. In this review, I outline the bidirectional nature of the cardio-metabolic interaction, with special emphasis on the impact that metabolic organs have on the cardiovascular system. I also discuss the contribution of the neural circuits and autonomic nervous system in mediating the crosstalk between cardiovascular and metabolic functions in health and disease, along with the molecular mechanisms involved.

INTRODUCTION

Overwelming clinical and experimental findings support the notion that metabolic processes exert tremedous influence on cardiovascular function. This is consistent with the essential role of the cardiovascular system in maintaining energy balance to preserve work output and efficiency of every organ in the body. The impact of the metabolism on cardiovascular regulation is more apparent in disease conditions such as obesity, with adipose tissue expansion causing a myriad of alterations that drive cardiovascular disease and poor health outcomes^1–5. The influence of metabolism on cardiovascular function is further supported by recent clinical trials that identified a robust cardiovascular benefit for semaglutide, a drug that targets the glucagon like peptide-1 (GLP-1) receptor which regulate glucose and energy homeostasis^6,7. Treating patients who were overweight or obese, with or without diabetes, with semaglutide led to a remarkable reduction in the risk of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke^8–13. This reduction in cardiovascular events may be related to the ability of semaglutide to improve many cardiovascular conditions (including hypertension, heart failure, and chronic kidney disease) characterized by autonomic dysfunction and excessive sympathetic drive. Remarkably, the magnitude of the benefit observed with semaglutide in the case of heart failure with preserved ejection fraction was much greater than that observed previously with other pharmacological therapies¹¹. Thus, these findings may mark the beginning of a new era in the management of cardiovascular disease using drugs that target metabolic processes.

Although the weight-reducing effect of semaglutide probably contributes to its beneficial cardiovascular effects, other mechanisms unrelated to weight loss seem to also play a role. This is supported by the observation that heart failure patients treated with semaglutide have a significant reduction in levels of N-terminal-pro-B-type natriuretic peptide^13,14. This suggests that semaglutide affects the heart directly, because body weight and N-terminal-pro-B-type natriuretic peptide typically have an inverse relationship, and lifestyle-mediated weight loss leads to an increase in levels of this peptide. Animal studies also showed that treatment with semaglutide induces a wider array of favorable cardiometabolic effects than does weight loss induced by pair-feeding¹⁵. In addition, the GLP-1 receptor was found to be present in the chemosensory cells of the carotid body, and its pharmacological activation led to lower discharge by the basal carotid artery, in association with attenuation of the blood pressure and sympathetic responses evoked by the chemoreflex¹⁶. Thus, the cardiovascular benefits of semaglutide are likely related, at least in part, to an ability to target specifically the pathobiology of cardiovascular disease.

The demonstration that patients with hypertension often exhibit both insulin resistance and a greater risk of developing type 2 diabetes than normotensive individuals highlight the pathological significance of the influence that the cardiovascular system has on metabolic processes¹⁷. Strikingly, population studies showed that each 20 mm Hg increase in systolic blood pressure is associated with a nearly 80% rise in risk of developing type 2 diabetes¹⁸. Conversely, lowering blood pressure prevented new-onset type 2 diabetes, with every 5 mm Hg decrease in systolic blood pressure reducing the risk of type 2 diabetes by 11%¹⁹. Interestingly, offspring born to patients who have essential hypertension were found to develop insulin resistance^20,21 pointing to the potential contribution of hypertension to the transgenerational diabetes risk²². Although the mechanisms that account for these shared features are not clear, they may relate to hypertension-associated changes in renal, vascular, and skeletal muscle tissue, as well as autonomic functions that impair glucose uptake and insulin sensitivity. Together, these findings represent strong evidence in support of the interconnectivity and bidirectionality of the crosstalk between metabolic and cardiovascular functions (Figure 1).

Figure 1:

Schematic representation of the two-way street nature of cardio-metabolic communication. Information emanating from afferent nerves and other systems including exosomes, that contain small non-coding RNA (snRNA), is integrated in the brain which exert tremendous influence on metabolism and cardiovascular function through the two branches of the autonomic nervous system (sympathetic and parasympathetic). Key forebrain and brainstem nuclei involved in cardio-metabolic crosstalk are depicted. ARC: arcuate nucleus of the hypothalamus, PVN: paraventricular nucleus of the hypothalamus, NTS: nucleus of the solitary tract, OVTL: organum vasculosum of the lamina terminalis, RVLM: rostroventrolateral medulla, SFO: subfornical organ, VMH: ventromedial hypothalamus.

METABOLIC IMPACT OF CARDIOVASCULAR ORGANS

Renal control of metabolism

The kidneys have long been known to play an important role in the metabolism of carbohydrates, proteins, lipids, and other nutrients²³. For instance, the kidneys reabsorb filtered glucose through sodium-glucose cotransporters 1 and 2 (SGLT 1 and 2). Within the kidney, proximal tubular cells not only clear glucose and insulin from the circulation, but also generate glucose through gluconeogenesis. Disruption of these functions may contribute to hypertension as well as to chronic kidney disease-associated renal dysfunction, hypoglycemia, and cachexia^24–26. This is supported by the observation that hypertension and the hemodynamic profile are improved after blockade of renal glucose reabsorption with SGLT2 inhibitors²⁷.

Vascular effects on metabolism

Through its action as metabolic gatekeeper, the vascular endothelium plays an essential role in metabolic homeostasis by controlling various processes including the delivery to, and storage of dietary lipids in, adipose tissue and providing fuel for vital organs such as the heart^28,29. Consequently, in addition to promoting insulin resistance, endothelial dysfunction can increase body weight and adiposity and cause hepatosteatosis³⁰. On the other hand, improvement in endothelium-dependent dilation in old mice lacking mTOR specifically in endothelial cells was shown to ameliorate glucose and lipid tolerance and to attenuate hepatic gluconeogenesis³¹. Dysfunction of sinusoidal endothelial cells in the liver has been implicated in the progression of nonalcoholic fatty liver disease via numerous mechanisms, including dysregulation of the inflammatory process, activation of hepatic stellate cells, augmentation of vascular resistance, and distortion of the microcirculation, resulting in the progression of nonalcoholic fatty liver disease^32,33.

Cardiac influence on systemic metabolism

The cardiac multiprotein complex Mediator, which regulate gene transcription, seems to have an important role in the regulation of systemic metabolism³⁴. Remarkably, while cardiac-specific loss- and gain-of-function of Mediator did not affect heart function it caused contrasting changes in body weight, energy expenditure, glucose metabolism, and plasma lipid levels³⁵. The mechanisms that underlie regulation of systemic metabolism by the cardiac Mediator remain elusive, but may involve the ability of the heart to modulate lipid metabolism in non-cardiac organs such as the liver, through the matrix metalloproteinase 2/C-C motif chemokine ligand 7/cardiac secretory phospholipase A2 axis^36,37. The myocardium also produces various microRNAs and humoral factors that have the potential to affect systemic metabolism, for example, the natriuretic peptide family of proteins and growth differentiating factors^37,38. Modulation of the autonomic nervous system by the cardiac afferent reflex represent another mechanism that can mediate the effect of the heart on metabolism^39–43. This possibility is supported by several studies implicating sympathetic traffic in heart failure associated cachexia caused by excess loss of adiposity^44,45. Remarkably, a prospective study identified muscle sympathetic nerve activity as the most sensitive marker of weight loss in heart failure patients⁴⁶. Moreover, heart failure patients treated with β-blockers displayed lower incidence of cachexia, and better outcomes^47,48. Together, these findings support a role for sympathetic nerve activation in the genesis of weight loss in the context of heart failure, presumably due to stimulation of energy expenditure and fat utilization. The contribution of the sympathetic nerves to the weight loss associated with other cardiovascular conditions such as stroke is worth investigating⁴⁹.

AUTONOMIC CONTROL OF CARDIOVASCULAR AND METABOLIC FUNCTIONS

Autonomic regulation of cardiovascular function

The autonomic nervous system is one of the main biological components that regulates homeostasis through its ability to affect every organ and function of the body. In particular, the interaction between its two branches—the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS)—has long been known to exert a tremendous influence on cardiovascular function including blood pressure⁵⁰. Activity of the SNS impacts blood pressure through the control of vascular resistance and cardiac output by affecting various processes including vascular reactivity, heart rate and contractility and the baroreceptor reflex. The SNS is also a key regulator of the renin-angiotensin system (RAS). Activity of the PNS has the opposite effect, promoting vasodilation and reducing the heart rate. The interaction between the SNS and PNS helps keep blood pressure within the normal range under various physiological conditions.

Autonomic dysregulation, particularly overactivation of the SNS, is a well-established driver of various cardiovascular diseases including hypertension, heart failure, and coronary artery disease⁵. For this reason, agents that target the SNS (such as β-blockers) are commonly used in the management of these conditions. More recently, catheter-based renal denervation emerged as a new and effective strategy to overcome resistant hypertension and other cardiovascular diseases characterized by heightened SNS activity^51,52.

Autonomic regulation of metabolism

The SNS plays a crucial role in regulating metabolism, and it does so by influencing various tissues and organs throughout the body (Figure 1). The overall metabolic effect of the SNS is to promote oxygen consumption and energy expenditure⁵³. To this end, it regulates key processes in adipose tissue (e.g., increasing thermogenesis and lipolysis), liver (e.g., promoting glycogenolysis), skeletal muscle (e.g., enhancing glucose metabolism and access to substrate), and pancreas (e.g., inhibiting insulin release)^54–56. Metabolic functions are also influenced by the PNS through its inhibition of hepatic glucose production, pancreatic release of insulin, stimulation of nutrient absorption and utilization by the digestive organs, such as the stomach and intestines, facilitation of glycogenesis in the liver and muscles, as well as lipogenesis in adipose tissue^43,54. It should be noted that the interplay between the SNS and PNS in metabolic homeostasis is dynamic and context dependent.

Abnormalities in the autonomic nervous system have been associated with obesity, diabetes, fatty liver disease, and other metabolic disorders. In the context of obesity, numerous studies have documented overactivation of SNS subserving metabolic organs such as adipose tissue and liver^57,58. This sympathetic activation to metabolic organs such as thermogenic brown adipose tissue is viewed a counterregulatory mechanism aimed at overcoming excess nutrients by promoting energy expenditure. However, an increase in metabolic SNS activity can be detrimental, as indicated by the observation that in obese mice hepatic sympathetic denervation has beneficial effects, reducing hepatic steatosis and improving the triglyceride profile, independent of changes in body weight and food intake⁵⁸. These findings indicate that in obesity, SNS overactivity represent a maladaptive response that contribute to the development of hepatic steatosis. Studies assessing the feasibility of disrupting overactive hepatic SNS activity as a new modality to treat metabolic diseases, including non-alcoholic fatty liver disease, are underway^55,59. Procedures that target the hepatic vagus nerve for the treatment of metabolic diseases are also being investigated^59,60.

AFFERENT NERVES AND CARDIO-METABOLIC CROSSTALK

Accumulating evidence points to the autonomic nervous system as an important mediator of the crosstalk between the cardiovascular function and metabolic homeostasis. This crosstalk is coordinated by the brain and autonomic nervous system (Figure 1). It should be noted that a nerve subserving a given organ can have a dual role, influencing both cardiovascular and metabolic functions. For instance, the renal sympathetic nerves, which are known to be critical for blood pressure control and the development of hypertension, have emerged as key regulators of glucose homeostasis, and shown to exert this effect by controlling the excretion of glucose in urine^61,62. Although the mechanisms underlying this dual control of metabolic and cardiovascular processes by the same nerve are unknown, this may involve the recruitment of different fibers. It is also possible that the cardiovascular and metabolic functions within the same organ (e.g., kidney) may respond to a different threshold of efferent nerve activity⁶³. Afferent renal nerves have also been implicated in metabolic regulation by promoting endogenous glucose production in response to glycosuria as loss of glucose in urine via renal GLUT2 is sensed as a biological threat^64,65. Together, these findings highlight the essential role of afferent and efferent renal nerves in glucose homeostasis with potential implications in diabetes.

Cardiovascular effects of metabolic vagal afferent nerves

The vagus nerve is recognized as a primary afferent pathway capable of transmitting information to the brain from peripheral organs. Afferent signals carried by this nerve convey information emanating from both the cardiovascular (e.g., heart) and metabolic (e.g., gastrointestinal track and liver) organs to the brainstem, where the information is processed and relayed to higher brain centers, such as the hypothalamus, which can then implement the necessary adjustments in the efferent activity of the SNS or PNS to produce the desired response. The intersection between the cardiovascular and metabolic autonomic systems is illustrated by the reflex decrease in vasomotor sympathetic traffic, blood pressure, and heart rate evoked by stimulation of the gastrointestinal afferent vagus nerve⁶⁶. A synergistic interaction between the gut hormone cholecystokinin (CCK) and the adipocyte-derived hormone leptin has emerged as an important mechanism that controls activity of the gastrointestinal afferent vagus nerve^67,68. This interaction may occur in the nodose ganglia vagal afferent neurons which express both CCK₁ receptor and leptin receptor⁶⁹. Interestingly, a reduction in the sensitivity of the afferent vagus nerve to gastric CCK and leptin has been shown to contribute to sympathetic activation and reduction in vasodilatory response in obese hypertensive rats, which may predispose to hypertension^70–72. The roles of other hormones that modulate afferent vagal nerve activity, such as GLP-1 and ghrelin⁷³, in the control of vasomotor sympathetic activity and hemodynamics remain to be determined. The contributions of gut sympathetic afferents to the control of these parameters under various conditions, including bariatric surgery, and in response to changes in the microbiome, are also worth investigating^74,75.

Pharmacological or surgical disruption of hepatic vagal afferent fibers also prevents glucocorticoid-induced hypertension, demonstrating that the contribution of the afferent fibers of the vagus nerve is not limited to the fibers emanating from the gut nor to cardiovascular risks associated with obesity⁷⁶. It should be noted, however, that in hypertensive animals, stimulation of the vagus nerve that activate both the efferent and afferent fibers (presumably including the hepatic afferents) decrease blood pressure and protects against endothelial dysfunction and aortic stiffening^77,78. There is also compelling evidence pointing to a beneficial effect of vagus nerve stimulation in the treatment of heart diseases, including heart failure, atrial fibrillation, diastolic dysfunction, myocardial fibrosis and arrhythmias^79–82. These beneficial cardiovascular effects of vagal nerve stimulation are likely mediated by the efferent fibers⁸³, but this remain to be demonstrated.

Cardiovascular effects of the adipose afferent reflex

The sensory nerves originating in white adipose tissue have been shown to induce a reflex suppression of efferent vagus nerve activity^84–86. This is associated with an increase in sympathetic activity that subserves metabolic organs such as white and brown tissues, liver, and pancreas, and it may represent an adaptive response that promotes energy expenditure and lipolysis. Surprisingly, capsaicin-mediated activation of the adipose afferent reflex was found to cause a significant increase in renal sympathetic nerve traffic and blood pressure, a response that can be blocked by denervation of the originating fat depot⁸⁷. Subsequent studies showed that an enhanced adipose afferent reflex contributes to obesity-associated sympathetic overactivity and hypertension⁸⁸. This is based on the enhanced baseline adipose afferent nerve activity, as well as the exaggerated responses induced by activation and inhibition of the adipose afferent reflex. Indeed, in obese hypertensive rats, a capsaicin-induced adipose afferent reflex evoked a greater increase in blood pressure and renal sympathetic tone than in controls. Conversely, in such rats selective sensory denervation of adipose tissue using resiniferatoxin caused a larger decrease in renal sympathetic nerve traffic and blood pressure, and this response lasted over three weeks.

Leptin, which increases renal sympathetic traffic and blood pressure by stimulating the adipose afferent reflex, was implicated as a driver of the enhanced baseline adipose afferent nerve activity in obesity^88,89. The actions of bradykinin and adenosine in adipose tissue have also been shown to cause a reflex increase in renal sympathetic nerve traffic and blood pressure by activating afferent sensory nerves^87,89. In addition, the adipose sensory reflex was implicated in early-life stress, based on an exaggerated increase in arterial pressure in response to stimulation of epididymal adipose tissue with capsaicin in high-fat diet male mice that had been subjected to maternal separation and early weaning⁹⁰. Interestingly, adipose sensory reflex-induced blood pressure increase in these mice is fat depot specific as capsaicin injection into subcutaneous adipose tissue did not elicit a response. Moreover, in these mice selective denervation of afferents emanating from the epididymal fat reduced blood pressure and attenuated the sympathetic index. Denervation of the kidneys also blunted the chronic blood pressure elevation and the acute capsaicin-induced pressor response in diet-obese mice exposed to early-life stress⁹⁰ implicating the renal nerves in mediating the changes displayed by these mice.

Interestingly, afferent nerves of perirenal adipose tissue were found to contribute to maintenance of pathological high blood pressure in lean spontaneous hypertensive rats (SHR). Specifically, the ablation or denervation of bilateral perirenal adipose tissue led to a long-lasting reduction in blood pressure and renal sympathetic nerve activity in SHR, but not in normotensive control rats⁹¹. An increase in levels of calcitonin gene-related peptide produced by dorsal root ganglia was identified as a mechanism that mediates the blood pressure and sympathetic lowering effect of perirenal adipose tissue ablation or denervation in SHRs. Together, these findings suggest that the adipose afferent reflex plays a pathophysiological role in various forms of hypertension, and that it does so through different pathways.

Various brain nuclei have been involved in mediating the adipose afferent reflex. An increase in cFos, a marker of neuronal activation, after activation of adipose afferents was documented in different nuclei, including the rostral ventrolateral medulla, organum vasculosum of the lamina terminalis, and paraventricular nucleus of the hypothalamus (PVN)^88,90. Adipose afferent reflex-induced increase in discharge activity of individual PVN neurons was confirmed using direct recording.⁹² Moreover, chemically mediated lesioning of the PVN neurons with kainic acid abolished the adipose afferent reflex induced by injection of capsaicin into the inguinal fat depot⁸⁷. At the molecular level, both N-methyl-D-aspartate receptors (NMDAR) and non-NMDAR, as well as NAD(P)H oxidase-derived superoxide anions, in the PVN, have been involved in mediating adipose afferent reflex and contribute to the tonic control of sympathetic outflow and blood pressure by this reflex^93,94. Insulin action in the PVN was implicated in the enhanced adipose afferent reflex and subsequent sympathetic activation in insulin resistance. This PVN action of insulin on the adipose afferent reflex response requires local melanocortin 4 receptors (MC4Rs)⁹⁵. However, the specific neuronal populations within the PVN that mediate the adipose afferent reflex response remains unknown.

CENTRAL NETWORK INVOLVED IN CARDIO-METABOLIC CROSSTALK

The brain plays an essential role in coordinating and mediating the communication between metabolism and cardiovascular function. In addition to the information carried by the afferent nerves discussed above, the brain receives various other signals from peripheral tissues and organs involved in the regulation of metabolic and cardiovascular functions. These various signals serve to inform the brain about the status of these functions. For instance, many hormones derived from organs that are implicated in metabolic regulation (e.g., adipose tissue, liver, pancreas, and gut) act in the brain to regulate energy blance through the control of food intake, energy expenditure, glucose homeosatsis, and lypolysis. The information emanating from various signals is processed in the brain before adjustments in the efferent output are made to restore homeosatasis. Importantly, the brain controls the activity of the efferent autonomic nerves in a specific manner. Indeed, the nerves that subserve each organ and tissue respond to brain action of various stimuli in distinct ways to restore homeostasis. However, the regional regulation of SNS outflows to cardiovascular and metabolic effectors can be detrimental in disease conditions such as obesity^96–99. The differential regulation of regional autonomic outflow in response to stimulation by reflex inputs and intrinsic changes in the brain under normal and pathologic conditions may be explained by the distinct molecular machineries, neuronal populations, and circuits that underlie the nerve activity subserving each organ^100–106.

Central mechanisms that mediate the effects of metabolism on cardiovascular function

The brain mechanisms underlying the influence of metabolism on the cardiovascular system includes the actions of metabolites such as free fatty acids, as well as hormones such as leptin, insulin and resistin. Regulation of the autonomic nervous system, and particularly SNS acitvity, has emerged as a major pathway by which the brain actions of these molecules regulate cardiovascular parameters including blood pressure. Moreover, preservation of the ability of metabolic hormones such as leptin and insulin to selectively activate sympathetic nerves in disease states such as obesity and type 2 diabetes is recognized as an important cause of the hypertension and other cardiovascular risks associated with these conditions^96,98,107. In-depth review of these aspects of cardio-metabolic communication have been reviewed extensively elswehere (e.g., refs^3,108,109).

Various neuronal populations have been implicated in mediating cardio-metabolic communication^110,111. For instance, the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic Agouti-related protein (AgRP) neurons of the arcuate nucleus of the hypothalamus which are key components of the melanocortin system have been thoroughly studied with regard to energy balance including sympathetic control of energy expenditure¹¹². Substantial studies including those using chemogenetics-mediated alteration of the activity of these two neuronal populations supports their importance for the regulation of blood pressure via the SNS^{110,113–115}. Furthermore, POMC neurons have been implicated in the hypertension associated with obesity by mediating the pressor actions of hormones such as leptin^104,110,116. Consistent with this, the downstream MC4R containing neurons particularly those located in the PVN and lateral hypothalamus were found to be critical for obesity-induced sympathetic activation and hypertension^117–120. Steroidogenic factor 1 (SF1) neurons located in the ventromedial hypothalamus is another neuronal population implicated in energy and glucose homeosatsis¹²¹ that contribute to the increase in sympathetic traffic and blood pressure in obesity⁹⁹. It should be noted, however, that each of the neuronal populations mentioned above are heterogenous and it is not clear whether the same neurons or different sub-populations are involved in metabolic vs cardiovascular regulation. A large number of other brain nuclei have been implicated in both metabolic and cardiovascular regulation, but the specific neuronal populations involved and their role in mediating cardio-metabolic crosstalk has not been defined.

Central mechanisms underlying cardiovascular influence on metabolism

An important emerging aspect of cardio-metabolic crosstalk relates to the metabolic effects of brain actions of hormones and other systems typically associated with cardiovascular regulation¹²². For instance, the brain RAS, which is best known for its major role in blood pressure regulation and the development of hypertension^123,124, has emerged as an important component of energy balance¹²⁵. Transgenic mice in which the brain RAS is selectively activated exhibit significant decreases in body weight and adiposity, features that are attributed to sympathetic activation of thermogenesis^126,127. Activation of the brain RAS was also implicated in the increase in energy expenditure evoked by deoxycorticosterone-salt treatment, in a manner independent of the elevation in blood pressure¹²⁸. Moreover, direct central administration of angiotensin II (Ang II) causes a robust increase in energy expenditure, leading to significant weight loss in rodents^129–132. Conversely, mice lacking the Ang II type 1a receptor (AT1aR) in the PVN displayed decreased energy expenditure, which resulted in excess adiposity¹³³.

The influence of the neuronal RAS on energy balance may relate to its role in mediating leptin-triggered regulation of energy balance. Indeed, pharmacological blockade of the brain angiotensin converting enzyme or AT1aR blunt leptin induced activation of thermogenic sympathetic traffic¹³⁴. In addition, AT1aR deletion in the subfornical organ interfered with the weight-reducing and thermogenic sympathetic actions of leptin¹³⁵. Selective deletion of AT1aR in leptin receptor-containing neurons also attenuated leptin’s ability to increase brown adipose tissue sympathetic traffic, thereby disrupting the adaptive response to an excess of calories and leading to excess weight gain without interfering with blood pressure responses to any of an array of stimuli¹³⁶. These phenotypes were recapitulated by AT1aR disruption in AgRP neurons, which represent a subset of the leptin-sensitive neurons. These findings point to the melanocortin system as a key mediator of the regulation of energy expenditure by the AT1aR. Consistent with this possibility, the effects of brain Ang II on energy expenditure depends on MC4R signaling, whereas fluid homeostasis and blood pressure responses were found to be independent of this signaling¹³². It should be noted, however, that changes in other neuronal systems, such as a decrease in hypothalamic expression of corticotrophin-releasing hormone (a neuropeptide known to control energy balance by regulating SNS activity) have also been identified as mechanisms with the potential to mediate the control of energy balance via neuronal AT1aR¹³³. Collectively, these findings indicate that the brain RAS controls energy homeostasis through its interaction with key systems involved in the regulation of energy expenditure.

The (pro)renin receptor (PRR) serves as a critical upstream element in the RAS. By activating its ligand, (pro)renin, the PRR plays a pivotal role in facilitating Ang II formation within the central nervous system. Interestingly, PRR was found to be expressed in various brain regions including neurons of PVN and the arcuate nucleus of the hypothalamus^137,138. Furthermore, high-fat diet fed mice lacking the neuronal PRR exhibit lower fasting blood glucose and improved glucose tolerance without changes in food intake, body weight, or insulin sensitivity¹³⁷. This phenotype may be explained by the reduced hypothalamic Ang II and subsequent protection from astrocyte dysfunction and activation of NF-κB signaling observed in high-fat diet fed PRR mice.

CONCLUSIONS AND PERSPECTIVES

Integrated functions of various body systems, including those involved in metabolic and cardiovascular regulation, require intricate mechanisms that are coordinated by the brain and autonomic nervous system. As discussed in this review, cardio-metabolic communication is a two-way street, and its dysfunction (including maladaptive activity of the autonomic nervous system in response to metabolic dysregulation) has emerged as a major cause of obesity-associated cardiovascular disease. Substantial evidence also points to the ability of the cardiovascular system to influence metabolic processes through a complex communication network that involves the autonomic nervous system. The pathophysiological significance of cardiovascular effects on metabolism is highlighted by the adverse outcome associated with the development of cachexia with the loss of fat mass in patients who experience chronic heart failure⁴⁴. However, there is still much work to be done to understand the full physiological and pathophysiological significance that cardiovascular organs have on metabolic function. Moreover, investigating the role of the autonomic nervous system in the detrimental metabolic effects of cardiovascular disease could identify novel therapeutic strategies. The potential sex difference in the cardio-metabolic communication is another area that needs to be assessed. Most of the work discussed above was performed in male animals whereas sexual dimorphism in autonomic, cardiovascular and metabolic physiology and disease sucsceptibilty is well established^139–141.

Brain-mediated coordination of cardio-metabolic crosstalk enables the rapid and appropriate adjustments that are necessary to maintain overall homeostasis of the body in the face of changes in internal and external demands and disturbances. However, little is known about the neural pathways involved in transduction of the sensory and vagal signals that emanate from peripheral metabolic and cardiovascular organs, and how the information is processed in the brain to evoke a response. Many nuclei and neuronal populations in the brain have been implicated in controlling the autonomic circuits that regulate both cardiovascular and metabolic functions. Yet, the extent of coupling/uncoupling of these brain neurocircuits remains unclear. Thus, more research is required to comprehensively grasp the central autonomic networks that mediate cardio-metabolic communication and the differential control of regional activity of the SNS and PNS in health and disease. Deciphering these mechanisms could expand our understanding of cardio-metabolic crosstalk and identify novel pathophysiological pathways underlying cardiovascular and/or metabolic diseases. This may eventually lead to improved treatments of these conditions. Indeed, one of the major hurdles in the development of anti-obesity drugs relate to their cardiovascular side effects including tachycardia and hypertension^120,142. Overcoming these adverse cardiovascular effects is challenging, but feasible¹⁴³. On the other hand, harnessing the beneficial cardiovascular effects of anti-obesity drugs such as the GLP-1 analogs will make it possible to kill many birds with one stone.