Through the past decade of research, the pathogenic mechanisms underlying metabolic syndrome have been suggested to involve not only the peripheral tissues, but also central metabolic regulation imbalances. The hypothalamus, and the arcuate nucleus in particular, is the control center for metabolic homeostasis and energy balance. Neuropeptide Y neurons are particularly abundantly expressed in the arcuate of the hypothalamus, where the blood-brain barrier is weak, such as to critically integrate peripheral metabolic signals with the brain center. Herein, focusing on metabolic syndrome, this manuscript aims to provide an overview of the regulatory effects of Neuropeptide Y on metabolic syndrome and discuss clinical intervention strategy perspectives for neurometabolic disease.
Metabolic syndrome (MS) is a disease characterized by obesity, dyslipidemia, high blood pressure, hyperglycemia, and insulin resistance. The increasing incidence of MS is a result of type 2 diabetes mellitus, cardiovascular disease (CVD), and other risk factors linked to early death. MS is a cluster of major health risk factors associated with increased incidence of type 2 diabetes and CVD. Although the definition and criteria for MS vary, all definitions include important risk factors, such as a large circumference, elevated blood pressure, low high-density lipoprotein level, elevated levels of triglycerides, and hyperglycemia.
The pathogenic mechanisms underlying MS are complicated. In the past, these have mainly focused on peripheral tissues. However, in recent years, it has been found that central metabolic regulation imbalance may play an essential role. As the body’s metabolic regulation center, the hypothalamus receives peripheral metabolic information, integrates peripheral signals, and regulates energy homeostasis by controlling a series of neuroendocrine functions. In the arcuate (Arc) nucleus of the hypothalamus, there are two major populations of neurons that regulate energy balance. One group expresses orexigenic neuropeptides, including neuropeptide Y (NPY) and Agouti-related peptide (AgRP), while the other expresses anorexigenic proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcripts (CART). NPY neurons, located in the Arc of the hypothalamus where the blood-brain barrier is weak, are involved in the central regulation of metabolic homeostasis and energy balance. Therefore, they are the first-line neurons of the brain to integrate peripheral metabolic signals to regulate food intake and energy expenditure. Arc NPY neurons secrete NPY, AgRP, and the neurotransmitter GABA; as such, they are also called NPY-AgRP-GABA neurons. NPY/AgRP neurons are glucose inhibited neurons, besides, they express insulin receptor (InsR) and leptin receptor (LepR), which can sense peripheral glucose and lipid metabolism signals. Arc NPY neurons project to other metabolic regulation-related nuclei, and thereafter through the autonomic nerve and endocrine system to centrally regulate metabolic balance. Arc NPY neuron response to peripheral metabolic alterations, increase food intake, decrease energy expenditure, and initiate ketogenesis. NPY is closely related to obesity and other metabolic diseases. Therefore, assessing the metabolic regulation function of Arc NPY neurons and their relationship with the physiological status of metabolic diseases has clinical significance for the prevention and treatment of metabolic-related diseases.
Neuropeptide Y was isolated from porcine hypothalamus for the first time in 1982. NPY is a 36-amino acid peptide and has 70% homology with peptide YY (PYY) and a 50% homology with pancreatic polypeptide (PP). As such, the three are classified into the same NPY family. NPY is an abundant peptide in the mammalian brain. In the central nervous system, NPY is widely distributed in various areas of the brain, with higher concentrations in the Arc of the hypothalamus, the paraventricular (PVN) nucleus of the hypothalamus, the supraoptic nucleus, the superior nucleus, median eminence, dorsal medial hypothalamic (DMH) nucleus, paraventricular thalamic nucleus, amygdala, hippocampus, nucleus tractus solitarius (NTS), locus coeruleus, nucleus accumbens and cerebral cortex. NPY is also expressed in the peripheral sympathetic nervous system and is stored and released together with norepinephrine.
Besides the liver, heart, spleen, kidney, urogenital tract, and vascular endothelial cells also express NPY. The distribution of NPY receptors is also widespread. NPY binds to receptors to activate specific signaling pathways and produce biological effects. To date, five NPY receptors have been successfully cloned from mammals, namely Y1, Y2, Y4, Y5, and Y6, which all belong to the family of G protein-coupled receptors. In the human central and peripheral nervous system, neuropeptide Y receptors are encoded by different genes and have different tissue distribution and intracellular signaling pathways, thereby indicating that the NPY system is involved in a variety of physiological processes and plays different roles in different physiological processes. Y1 receptor is critical to feeding behavior. Studies have shown that selective NPY-Y1 and NPY Y5 receptor agonists strongly promote feeding behaviors. Furthermore, the increased expression of Y2 and Y4 receptors will produce anorexia effects. Y2 receptor knockout model was found to have weight gain, fat deposition and hyperorexia. Y4 receptor knockout mice displayed a thin phenotype with lower body weight.
Studies have documented the effect of central NPY on energy homeostasis, alongside the molecular mechanisms underlying these effects, including central and peripheral signaling pathways.
Central NPY neurons can integrate peripheral metabolic signals via neural pathways for regulating energy homeostasis.
Neuropeptide Y mainly functions as a sympathetic co-transmitter. NPY not only co-locates in neurons with other neurotransmitters (such as norepinephrine) but is also synthesized and released by non-neuronal cells. The traditional neurotransmitter norepinephrine and non-adrenergic transmitter adenosine triphosphate are stored in a large vesicle pool with small dense core vesicles, while NPY is stored in a small vesicle pool with large dense core vesicles, co-localized with norepinephrine. Although multiple neurotransmitters exist in the same vesicle, their release patterns are different due to the varying doses of neurotransmitters at the ends of axons and the activation of sympathetic nerves. For example, studies have shown that although adenosine triphosphate and norepinephrine co-locate in vesicles, the doses of adenosine triphosphate and norepinephrine in each vesicle may be uneven, due to the stimulation intensity of the sympathetic nervous system. Adenosine triphosphate and norepinephrine are mainly released under low-frequency activation of the sympathetic nerve, while NPY is released in response to strong, continuous and high-frequency activation of the sympathetic nerve.
Neuropeptide Y neurons projected to the PVN. The PVN is adjacent to the top of the third ventricle and is an important endocrine and metabolic regulation nucleus. Damage to PVN can lead to obesity. Single-minded-1 neuron (SIM-1) in PVN highly expresses melanocortin 3/4 receptor (MC3/4R), which is activated by α-melanocyte-stimulating hormone (α-MSH) and inhibits food intake. MC4R knockout can increase appetite and increase food intake. Activating the projection of PVN to the ventromedial nucleus of the hindbrain (VMH), the vagus nerve complex and locus coeruleus (LC) can also inhibit food intake. PVN neurons secrete corticotropin-releasing factor (CRF) and oxytocin (OXT), both of which inhibit food intake. NPY neuron-PVN is a classic neural pathway that integrate metabolic signals and to convey information from the ARC to other brain areas involved in appetite regulation and energy homeostasis.
Neuropeptide Y/AgRP neurons release NPY to PVN neurons. At the same time, POMC neurons cleave and release α-MSH, an anorexigenic peptide that binds to and activates MC3/4R. α-MSH combines with MC3/4R in PVN neuron and functions to inhibit food intake, while NPY antagonizes the effect of α-MSH and increases food intake.
Arcuate NPY neurons project to PVN tyrosine hydroxylase (TH)-expressing neurons, reducing Y1 receptor-mediated TH expression, thereby reducing sympathetic activity and brown adipose tissue (BAT) thermogenesis and modulating energy expenditure. Increased NPY expression in the ARC under fasting, stress, or chronic-overfeeding conditions, acting via PVN Y1 receptors, results in the inhibition of TH tonus and sympathetically innervated BAT thermogenesis by downregulating uncoupling protein 1(UCP1) expression in BAT.
Arcuate NPY neurons also release NPY to PVN thyrotropin-releasing hormone (TRH) positive neurons under peripheral metabolic signals, such as ghrelin, and bind to Y1/Y5 receptors, inhibit cAMP-PKA signal, reduce TRH gene transcription, and reduce thyroid hormone release. If this process is dysfunctional, this will result in the inhibition of thyroid hormone release, which will indirectly decrease glucagon secretion and impair the function of pancreatic β cells and type 1 diabetes via the autonomic nervous system.
The NPY-PVN OXT projection is involved in the initiation of food intake. NPY neurons release GABA and NPY to OXT-positive neurons in PVN, activate GABA A receptors and NPY-Y1-cAMP-PKA pathways, respectively, thereby inhibiting OXT neurons and reducing the release of oxytocin. This thereafter increases appetite, decreases basal metabolic rate and decreases bone synthesis rate.
Corticotropin-releasing factor neurons in the hypothalamic PVN initiate hypothalamic–pituitary–adrenal axis activity through the release of CRF into the portal system. The recent discovery of neurons expressing CRF receptor type 1 (CRFR1), the primary receptor for CRF, adjacent to CRF neurons within the PVN, suggests that CRF also signals within the hypothalamus to coordinate aspects of the stress response. CRFR1 neur
