Neuropeptide Y suppresses thermogenic and cardiovascular sympathetic nerve activity via Y1 receptors in the paraventricular nucleus and dorsomedial hypothalamus

Abstract

In hungry animals, neuropeptide Y (NPY) neurones in the arcuate nucleus (ArcN) are activated to suppress energy expenditure, in part by decreasing brown adipose tissue sympathetic nerve activity (BAT SNA); however, the NPY receptor subtype and brain neurocircuitry are unclear. In the present study, we investigated the inhibition of BAT SNA by exogenous and endogenous NPY via binding to Y1 receptors (NPY1R) in the hypothalamic paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH), in anaesthetised male rats. Downstream projections of PVN/DMH NPY1R‐expressing neurones were identified using male Npy1r‐cre mice and localised unilateral DMH or PVN injections of an adeno‐associated virus, which allows for the cre‐dependent expression of a fluorescent protein (mCherry) in the cell bodies, axon fibres and nerve terminals of NPY1R‐containing neurones. Nanoinjections of NPY into the DMH of cooled rats decreased BAT SNA, as well as mean arterial pressure (MAP) and heart rate (HR), and these responses were reversed by subsequent injection of the selective NPY1R antagonist, BIBO3304. In warmed rats, with little to no BAT SNA, bilateral nanoinjections of BIBO3304 into the DMH or PVN increased BAT SNA, MAP and HR. DMH NPY1R‐expressing neurones projected heavily to the raphe pallidus (RPa), which houses BAT presympathetic neurones, as well as the PVN. In anaesthetised mice, DMH BIBO3304 increased splanchnic SNA, MAP and HR, all of which were reversed by nonselective blockade of the PVN with muscimol, suggesting that DMH‐to‐PVN connections are involved in this DMH BIBO3304 disinhibition. PVN Y1R expressing neurones also projected to the RPa, as well as to the nucleus tractus solitarius. We conclude that NPY tonically released in the DMH and PVN suppresses BAT SNA, MAP and HR via Y1R. Downstream neuropathways for BAT SNA may utilise direct projections to the RPa. Release of tonic NPY inhibition of BAT SNA may contribute to feeding‐ and diet‐induced thermogenesis.

Profiling of G-protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

“…Chemokines and chemokine receptors have long been associated with obesity-linked inflammation and insulin resistance and modulation of the chemokine/Chemokine receptor axis is considered a novel approach for the treatment of obesity and associated metabolic disorders (31)(32). Similarly, previous studies have reported increased expression of NPYR1 expression in adipose tissue of obese human subjects and high-fat diet-fed mice (34)(35). Moreover, selective antagonism of pe-ripheral NPYR1 was shown to prevent insulin resistance and other metabolic abnormalities in high-fat diet-fed mice (36)(37).…”

“…Many GPCRs in this list have previously been studied for their role in adipose biology. These include alpha-and beta-adrenergic receptors (11)(12)(13)(14)(15)(16), adenosine receptors (19), free fatty acid receptors (7,17,18), adhesion receptors (20,21), hydroxycarboxylic acid receptors (22,23), gastric inhibitory peptide (27)(28)(29), chemokine receptors (30)(31) and many others (32)(33)(34)(35). Interestingly, many GPCRs with notable expression profiles in adipose tissue and adipocytes have no known role in adipose metabolism.…”

Role of Dorsomedial Hypothalamus GABAergic Neurons in Sleep–Wake States in Response to Changes in Ambient Temperature in Mice

“…DMH is a heterogeneous nucleus containing orexin-expressing, glutamatergic, cholinergic [17], and GABAergic neurons, which can also be divided into many subtypes, such as galaninergic-expressing [23] and neuropeptide Y [35]. There are a large number of orexin neurons in the DMH [36], which also intensively project with the median preoptic nucleus and send projections to the ventrolateral preoptic nucleus, an important sleep regulation center [24], and the LH, the main arousal regulation center.…”

An integrated single‐cell RNA‐seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types

“…These genes have been associated with feeding behavior, suggesting the Brs3-Adarb2 population to be involved in the control of feeding behavior. 35,[38][39][40][41][42] Interestingly, Mc4r, Brs3, Npy1r, and Vgf have also been associated with regulating energy expenditure through the sympathetic nervous system, 35,42,43 suggesting the Brs3-Adarb2 population to also be involved in sympathetic outflow. This indicates that at least part of the preautonomic neurons may also project centrally, which further highlights the difficulty in comprehensively classifying the central projections of the PVN.…”