Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus

Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks’ refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.     

Melanocortin receptors mediate the excitatory effects of blood-borne murine leptin on hypothalamic paraventricular neurons in rat

The central pathways and mediators involved in sympathoexcitatory responses to circulating leptin are not well understood, although the arcuate-paraventricular nucleus (ARC-PVN) pathway likely plays a critical role. In urethane-anesthetized rats, ipsilateral intracarotid artery (ICA) injection of murine leptin (100 microg/kg) activated most PVN neurons tested. These responses were reduced by intracerebroventricular injection of the melanocortin subtype 3 and 4 receptor (MC3/4-R) antagonist SHU-9119 (0.6 nmol). The MC3/4-R agonist MTII (0.6 nmol icv) activated PVN neurons. Some PVN neurons that were excited by ICA leptin were inhibited by local application of neuropeptide Y (NPY, 2.5 ng). ICA leptin (100 microg/kg) excited presympathetic rostral ventrolateral medulla neurons and renal sympathetic nerve activity without significant change in blood pressure or heart rate; these effects were mimicked by intracerebroventricular injection of MTII (0.6 nmol). These data provide in vivo electrophysiological evidence to support the hypothesis that circulating leptin activates the sympathetic nervous system by stimulating the release of alpha-melanocyte-stimulating hormone in the vicinity of PVN neurons that are inhibited by the orexogenic peptide NPY.     

Viral mediated neuropeptide Y expression in the rat paraventricular nucleus results in obesity

Objective: Chronic central administration of neuropeptide Y (NPY) has dramatic effects on energy balance; however, the exact role of the hypothalamic paraventricular nucleus (PVN) in this is unknown. The aim of this study was to further unravel the contribution of NPY signaling in the PVN to energy balance. Research Methods and Procedures: Recombinant adeno‐associated viral particles containing NPY (rAAV‐NPY) were injected in the rat brain with coordinates targeted at the PVN. For three weeks, body weight, food intake, endocrine parameters, body temperature, and locomotor activity were measured. Furthermore, effects on insulin sensitivity and expression of NPY, agouti‐related protein (AgRP), and pro‐opiomelanocortin in the arcuate nucleus were studied. Results: Food intake was increased specifically in the light period, and dark phase body temperature and locomotor activity were reduced. This resulted in obesity characterized by increased fat mass; elevated plasma insulin, leptin, and adiponectin; decreased AgRP expression in the arcuate nucleus; and decreased insulin sensitivity; whereas plasma corticosterone was unaffected. Discussion: These data suggest that increased NPY expression targeted at the PVN is sufficient to induce obesity. Interestingly, plasma concentrations of leptin and insulin were elevated before a rise in food intake, which suggests that NPY in the PVN influences leptin and insulin secretion independently from food intake. This strengthens the role of the PVN in regulation of energy balance by NPY.     

NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways

Fasting-induced suppression of the hypothalamic-pituitary-thyroid (HPT) axis is an adaptive response to decrease energy expenditure during food deprivation. Previous studies demonstrate that leptin communicates nutritional status to the HPT axis through thyrotropin-releasing hormone (TRH) in the paraventricular nucleus (PVN) of the hypothalamus. Leptin targets TRH neurons either directly or indirectly via the arcuate nucleus through pro-opiomelanocortin (POMC) and agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons. To evaluate the role of these pathways in vivo, we developed double knockout mice that lack both the melanocortin 4 receptor (MC4R) and NPY. We show that NPY is required for fasting-induced suppression of Trh expression in the PVN. However, both MC4R and NPY are required for activation of hepatic pathways that metabolize T₄ during the fasting response. Thus, these signaling pathways play a key role in the communication of fasting signals to reduce thyroid hormone levels both centrally and through a peripheral hepatic circuit.     

Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat

Energy stores are held relatively constant in many mammals. The circuitry necessary for maintaining energy homeostasis should (1) sense the amount of energy stored in adipose tissue, (2) sense and integrate the multiple opposing signals regarding nutritional state, and (3) provide output regulating energy intake and expenditure to maintain energy homeostasis. We demonstrate that individual neurons within the paraventricular nucleus of the hypothalamus (PVH) are capable of detection and integration of orexigenic (neuropeptide Y [NPY]) and anorexigenic (melanocortin) signals, that NPY and melanocortins are functional antagonists of each other within the PVH in the regulation of feeding behavior, and that melanocortin administration within the PVH regulates both feeding behavior and energy expenditure. These data provide a cellular basis for the adipostat within neurons in the PVH that appear to be jointly regulated by NPY- and melanocortin-responsive neurons.     

The hypothalamic paraventricular nucleus is not essential for orexigenic NPY or anorexigenic melanocortin action

Bilateral electrolytic lesions of the paraventricular nucleus of the hypothalamus (PVN) produce hyperphagia with excess weight gain. The orexigenic neuropeptide Y (NPY) system and the anorexigenic melanocortin system act in the PVN to regulate food intake, and participate in mediating the anorexic effects of leptin. We hypothesized that changes in the responsiveness of these systems may contribute to the hyperphagia observed in PVN-lesioned rats. Adult female Sprague-Dawley rats received either sham or electrolytic lesions in the PVN immediately followed by implantation of a guide cannula into the third cerebroventricle. Twenty-five days following surgery groups of sham and hyperphagic PVN-lesioned rats were injected intracerebroventricularly (i.c.v.) with either 118 pmole or 470 pmole of NPY and food intake was measured for 3 h. Food intake in response to NPY was nearly three-fold higher in PVN-lesioned rats as compared to sham rats. However, the response to 5 microg leptin i.c.v. was not different in lesioned versus sham rats. The effect of the melanocortin agonist MTII on food intake was tested in additional rats beginning either 7-14 days or 30-40 days following surgery. Doses of 0.1 nmole or 1.0 nmole of MTII were injected immediately before lights-off and food intake was measured at 2 h, 24 h and 48 h post-injection. Suppression of food intake in PVN-lesioned rats was not different from that in sham-lesioned rats. These data suggest that hyper-responsiveness to NPY may account in part for the hyperphagia observed in PVN-lesioned rats. Furthermore, based on the similarities of responses of PVN-lesioned and sham control rats to the anorexigenic agents MTII and leptin and the hypersensitivity of lesioned rats to NPY, we conclude that the PVN is not essential for NPY stimulation of food intake or for melanocortin suppression of food intake and that NPY and melanocortin receptors outside of the PVN are sufficient to produce these effects.     

Activation of the melanocortin-4 receptor causes enhanced excitation in presympathetic paraventricular neurons in obese Zucker rats

Sympathetic nerve activity is increased in obesity-related hypertension. However, the central mechanisms involved in the increased sympathetic outflow remain unclear. The hypothalamic melanocortin system is important for regulating energy balance and sympathetic outflow. To understand the mechanisms by which the melanocortin systems regulates sympathetic outflow, we investigated the role of melanocortin 4 receptors (MC4R) in regulating presympathetic paraventricular nucleus (PVN) neurons. We performed whole-cell patch-clamp recordings on retrogradely labeled PVN neurons projecting to the rostral ventrolateral medulla in brain slices from obese zucker rats (OZRs) and lean zucker rats (LZRs). The MC4R agonists melanotan II (MTII) and α-melanocyte-stimulating hormone (α-MSH) increased the firing activity and depolarized the labeled PVN neurons from both LZRs and OZRs in a concentration-dependent manner. MTII produced significant greater increase in the firing activity in OZRs than in LZRs. Blocking MC4R with the specific antagonist SHU9119 had no effect on the basal firing rate but abolished the MTII-induced increase in the firing rate in both OZRs and LZRs. Furthermore, intracellular dialysis of guanosine 5'-O-(2-thodiphosphate), but not bath application of kynurenic acid and bicuculline, eliminated the MTII-induced increase in firing activity. In addition, MTII had no effect on the frequency and amplitude of glutamatergic excitatory postsynaptic currents and GABAergic inhibitory postsynaptic currents in labeled PVN neurons. Collectively, our findings suggest that MC4R contributes to the elevated excitability of PVN presympathetic neurons, which may be involved in obesity-related hypertension.     

Leptin sensitive neurons in the hypothalamus.

A major paradigm in the field of obesity research is the existence of an adipose tissue-brain endocrine axis for the regulation of body weight. Leptin, the peptide mediator of this axis, is secreted by adipose cells. It lowers food intake and body weight by acting in the hypothalamus, a region expressing an abundance of leptin receptors and a variety of neuropeptides that influence food intake and energy balance. Among the most promising candidates for leptin-sensitive cells in the hypothalamus are arcuate nucleus neurons that co-express the anabolic neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), and those that express proopiomelanocortin (POMC), the precursor of the catabolic peptide, alphaMSH. These cell types contain mRNA encoding leptin receptors and show changes in neuropeptide gene expression in response to changes in food intake and circulating leptin levels. Decreased leptin signaling in the arcuate nucleus is hypothesized to increase the expression of NPY and AGRP. Levels of leptin receptor mRNA and leptin binding are increased in the arcuate nucleus during fasting, principally in NPY/AGRP neurons. These findings suggest that changes in leptin receptor expression in the arcuate nucleus are inversely associated with changes in leptin signaling, and that the arcuate nucleus is an important target of leptin action in the brain.     

Role of melanocortin signaling in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis

The melanocortin signaling system is orchestrated by two, independent groups of neurons in the hypothalamic arcuate nucleus with opposing functions that synthesize either alpha-melanocyte stimulating hormone (alpha-MSH) or agouti-related protein (AGRP). These neurons exert regulatory control over hypophysiotropic TRH neurons in the hypothalamic paraventricular nucleus (PVN) at least in part through direct, overlapping, monosynaptic projections to the PVN. Alpha-MSH has an activating effect on hypophysiotropic TRH neurons via the phosphorylation of CREB, and when administered exogenously, can completely reverse fasting-induced suppression of TRH mRNA in the PVN. AGRP has a potent inhibitory effect on the hypothalamic-pituitary-thyroid axis in normally fed animals, mediated through actions at melanocortin 4 receptors. Inhibition of the HPT axis by fasting may be explained by inhibition of melanocortin signaling as a result of a reduction in alpha-MSH and increase in AGRP. Neuropeptide Y may also modulate the effects of the melanocortin signaling system during fasting by potentiating the inhibitory actions of AGRP on hypophysiotropic TRH neurons to prevent the phosphorylation of CREB and through direct inhibitory effects on alpha-MSH-producing neurons in the arcuate nucleus.     

The renin-angiotensin-aldosterone system excites hypothalamic paraventricular nucleus neurons in heart failure

The paraventricular nucleus (PVN) of the hypothalamus has critical homeostatic functions, including the regulation of fluid balance and sympathetic drive. It has been suggested that altered activity of this nucleus contributes to the progression of congestive heart failure (HF). We hypothesized that forebrain influences of the renin-angiotensin-aldosterone system augment the activity of PVN neurons in HF. The rate of PVN neurons (n = 68) from rats with ischemia-induced HF was higher than that of PVN neurons (n = 42) from sham-operated controls (8.7 +/- 0.8 vs. 2.7 +/- 0.3 spikes/s, P < 0.001, HF vs. SHAM). Forebrain-directed intracarotid artery injections of the angiotensin type 1 receptor antagonist losartan, the angiotensin-converting enzyme inhibitor captopril, and the mineralocorticoid receptor antagonist spironolactone all significantly (P < 0.05) reduced PVN neuronal activity in HF rats. These findings demonstrate that the renin-angiotensin-aldosterone system drives PVN neuronal activity in HF, likely resulting in increased sympathetic drive and volume accumulation. This mechanism of neurohumoral excitation in HF is accessible to manipulation by blood-borne therapeutic agents.     

Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei

Ghrelin is a 28-amino acid acylated peptide and is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The GHS-R is expressed in hypothalamic nuclei, including the arcuate nucleus (Arc) where it is colocalized with neuropeptide Y (NPY) neurons. In the present study, we examined the effects of ghrelin on feeding and energy substrate utilization (respiratory quotient; RQ) following direct injections into either the arcuate or the paraventricular nucleus (PVN) of the hypothalamus. Ghrelin was administered at the beginning of the dark cycle at doses of 15-60 pmol to male and female rats. In feeding studies, food intake was measured 2 and 4 h postinjection. Separate groups of rats were injected with ghrelin, and the RQ (VCO(2)/VO(2)) was measured using an open circuit calorimeter over a 4-h period. Both Arc and PVN injections of ghrelin increased food intake in male and female rats. Ghrelin also increased RQ, reflecting a shift in energy substrate utilization in favor of carbohydrate oxidation. Because these effects are similar to those observed after PVN injection of NPY, we then assessed the impact of coinjecting ghrelin with NPY into the PVN. When rats were pretreated with very low doses of ghrelin (2.5-10 pmol), NPY's (50 pmol) effects on eating and RQ were potentiated. Overall, these data are in agreement with evidence suggesting that ghrelin functions as a gut-brain endocrine hormone implicated in the regulation of food intake and energy metabolism. Our findings are also consistent with a possible interactive role of hypothalamic ghrelin and NPY systems.     

Neuropeptide Y content in the hypothalamic paraventricular nucleus responds to fasting and refeeding in broiler chickens

To examine the neural mechanism by which hypothalamic neuropeptide Y (NPY) regulates energy homeostasis and feeding behavior in commercial broilers, we measured NPY content in several hypothalamic regions of birds that were fasted and then refed. After fasting for 48 and 72 h, body weight significantly decreased, and food intake significantly increased during the subsequent refeeding. The lost body weight was not restored to ad libitum feeding levels even after 3 days of refeeding. Plasma glucose concentration and body fat content significantly decreased and plasma non-esterified fatty acid (NEFA) concentration significantly increased after 48- and 72-h fasting. Refeeding for 24 h restored plasma metabolites and body fat content to pre-fasting levels. NPY content in the paraventricular nucleus (PVN) and infundibular nucleus significantly increased during fasting, and NPY content of the PVN was restored to pre-fasting levels after 24-h refeeding. However, there was no significant change in the NPY content of the lateral hypothalamic area during fasting or refeeding. The present results of changes in the hypothalamic NPY content during fasting and refeeding support the hypothesis that NPY plays a central role in regulation of energy homeostasis, with especially important effect on feeding behavior and body weight in broiler chickens.     

Cardiovascular Responses to Chemical Stimulation of the Hypothalamic Arcuate Nucleus in the Rat: Role of the Hypothalamic Paraventricular Nucleus

The mechanism of cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus (ARCN) was studied in urethane-anesthetized adult male Wistar rats. At the baseline mean arterial pressure (BLMAP) close to normal, ARCN stimulation elicited decreases in MAP and sympathetic nerve activity (SNA). The decreases in MAP elicited by ARCN stimulation were attenuated by either gamma-aminobutyric acid (GABA), neuropeptide Y (NPY), or beta-endorphin receptor blockade in the ipsilateral hypothalamic paraventricular nucleus (PVN). Combined blockade of GABA-A, NPY1 and opioid receptors in the ipsilateral PVN converted the decreases in MAP and SNA to increases in these variables. Conversion of inhibitory effects on the MAP and SNA to excitatory effects following ARCN stimulation was also observed when the BLMAP was decreased to below normal levels by an infusion of sodium nitroprusside. The pressor and tachycardic responses to ARCN stimulation at below normal BLMAP were attenuated by blockade of melanocortin 3/4 (MC3/4) receptors in the ipsilateral PVN. Unilateral blockade of GABA-A receptors in the ARCN increased the BLMAP and heart rate (HR) revealing tonic inhibition of the excitatory neurons in the ARCN. ARCN stimulation elicited tachycardia regardless of the level of BLMAP. ARCN neurons projecting to the PVN were immunoreactive for glutamic acid decarboxylase 67 (GAD67), NPY, and beta-endorphin. These results indicated that: 1) at normal BLMAP, decreases in MAP and SNA induced by ARCN stimulation were mediated via GABA-A, NPY1 and opioid receptors in the PVN, 2) lowering of BLMAP converted decreases in MAP following ARCN stimulation to increases in MAP, and 3) at below normal BLMAP, increases in MAP and HR induced by ARCN stimulation were mediated via MC3/4 receptors in the PVN. These results provide a base for future studies to explore the role of ARCN in cardiovascular diseases.     

生后雌性小鼠下丘脑室旁核内ER—β表达的免疫组化研究

研究发现小鼠下丘脑室旁核(PVN)内雌激素β受体(ER-β)的表达与在大鼠等一些实验动物脑PVN的表达有差异,提示其在小鼠PVN内的表达可能有特定的生理意义。为了深入探讨ER—β在小鼠PVN内的功能,本文采用硫酸镍铵增强显色的免疫组化SP法研究了ER—β在生后雌性小鼠PVN内的表达。结果发现ER—β免疫阳性物质主要见于PVN的大细胞部,在小细胞部和背侧帽部免疫阳性细胞数目较少。免疫阳性物质主要位于细胞核内,未发现明显的胞浆或突起阳性,但在发育的某些时期可见免疫阳性细胞核局部呈现阴性反应。最高表达见于生后早期(第1—9天),随后表达降低,生后一个月即达到成年水平。PVN内ER-β的表达模式表现为生后早期表达高、随后降低,提示在该部位ER—β可能主要参与了对生后早期PVN的神经内分泌活动以及神经结构的发育与完善的调控,并可能与生后早期动物的应激、体重增加和脂肪代谢等有关。     

Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats

Ghrelin, the endogenous growth hormone secretagogue, has an important role in metabolic homeostasis. It exists in two major molecular forms: acylated (AG) and unacylated (UAG). Many studies suggest different roles for these two forms of ghrelin in energy balance regulation. In the present study, we compared the effects of acute intracerebroventricular administration of AG, UAG and their combination (AG+UAG) to young adult Wistar rats on food intake and central melanocortin system modulation. Although UAG did not affect food intake it significantly increased the number of c-Fos positive neurons in the arcuate (ARC), paraventricular (PVN) and solitary tract (NTS) nuclei. In contrast, UAG suppressed AG-induced neuronal activity in PVN and NTS. Central UAG also modulated hypothalamic expression of Mc4r and Bmp8b, which were increased and Mc3r, Pomc, Agrp and Ucp2, which were decreased. Finally, UAG, AG and combination treatments caused activation of c-Fos in POMC expressing neurons in the arcuate, substantiating a physiologic effect of these peptides on the central melanocortin system. Together, these results demonstrate that UAG can act directly to increase neuronal activity in the hypothalamus and is able to counteract AG-induced neuronal activity in the PVN and NTS. UAG also modulates expression of members of the melanocortin signaling system in the hypothalamus. In the absence of an effect on energy intake, these findings indicate that UAG could affect energy homeostasis by modulation of the central melanocortin system.     

Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration

The paraventricular nucleus (PVN) of the hypothalamus is known to modulate feeding, obesity, and ethanol intake. Neuropeptide-Y (NPY), which is released endogenously by neurons projecting from the arcuate nucleus to the PVN, is one of the most potent stimulants of feeding behavior known. The role of NPY in the PVN on ethanol self-administration is unknown. To address this issue, rats were trained to self-administer ethanol via a sucrose fading procedure and injector guide cannulae aimed at the PVN were surgically implanted. Microinjections of NPY and NPY antagonists in the PVN were conducted prior to ethanol self-administration sessions. All doses of NPY significantly increased ethanol self-administration and preference, and decreased water intake. The NPY antagonist D-NPY partially reduced ethanol self-administration and completely blocked the effects of an intermediate dose of NPY (10 fmol) on ethanol intake, preference, and water intake. The competitive non-peptide Y1 receptor antagonist BIBP 3226 did not significantly alter ethanol self-administration or water intake when administered alone in the PVN but it completely blocked the effect of NPY (10 fmol) on ethanol intake. NPY infused in the PVN had no effect on ethanol self-administration when tested in rats that did not have a long history of ethanol self-administration. The doses of NPY tested produced no effect on food intake or body weight measured during the 24-h period after infusion in either ethanol-experienced or ethanol-inexperienced rats. These results indicate that elevation of NPY levels in the PVN potently increases ethanol self-administration and that this effect is mediated through NPY Y1 receptors.     

Prepro-orexin and feeding-related peptide receptor expression in dehydration-induced anorexia

Food-restricted animals present metabolic adaptations that facilitate food-seeking behavior and decelerate energy utilization by reducing the hypothalamus–pituitary–thyroid (HPT) axis function. Stress by dehydration induces an anorexic behavior in rats, loss of weight and reduced food intake when compared to ad libitum fed animals, however these alterations are accompanied by HPT axis changes such as increased serum thyrotropin levels and enhanced expression of thyrotropin-releasing hormone (TRH) in the paraventricular nucleus of the hypothalamus, which is considered as anorexigenic peptide. In contrast, a pair-fed group conformed by forced-food-restricted animals (FFR) (eating the exact same amount of food as dehydration-induced anorexic rats—DIA rats) present decreased TRH mRNA levels. NPY synthesis in the arcuate nucleus and orexin-expressing neurons from the lateral hypothalamic area (LHA) are activated during food restriction. These brain structures project into PVN, suggesting that NPY and orexins are possible factors involved in TRHergic neuron activation in DIA rats. Leptin signaling is another likely factor to be involved in TRH differential expression. Therefore, to gain more insight into the regulation of the feeding behavior in the experimental models, we analyzed Y1, Y5, Ox1-R and Ob-R_b mRNA levels in PVN and prepro-orexin in LHA, since their signaling to the PVN might be altering TRH synthesis and feeding in DIA animals. Prepro-orexinergic cells were activated in FFR animals; Ox1-R and Y1 expression was reduced in FFR vs. controls or DIA group. Compensatory changes in PVN receptor expression of some feeding-related peptides in anorexic rats may alter TRHergic neural response to energy demands.     

Regulation of thermogenesis by the central melanocortin system

Adaptive thermogenesis represents one of the important homeostatic mechanisms by which the body maintains appropriate levels of stored energy and its core temperature. Dysregulation of adaptive thermogenesis promotes obesity. The central melanocortin system, in particular the melanocortin 4 receptor (MC4R) signaling pathway, influences the regulation of every aspect of energy balance, including thermogenesis, and plays a critical role in energy homeostasis in both rodent and man. This review will outline our current understanding of adaptive thermogenesis, focusing on the role of the central melanocortin pathway in the regulation of thermogenesis.     

Whole-brain patterns of the presynaptic inputs and axonal projections of BDNF neurons in the paraventricular nucleus

Brain-derived neurotrophic factor (BDNF) plays a crucial role in human obesity. Yet, the neural circuitry supporting the BDNF-mediated control of energy homeostasis remains largely undefined. To map key regions that might provide inputs to or receive inputs from the paraventricular nucleus (PVN) BDNF neurons, a key type of cells in regulating feeding and thermogenesis, we used rabies virus-based transsynaptic labeling and adeno-associated virus based anterograde tracing techniques to reveal their whole-brain distributions. We found that dozens of brain regions provide dense inputs to or receive dense inputs from PVN BDNF neurons, including several known weight control regions and several novel regions that might be functionally important for the BDNF-mediated regulation of energy homeostasis.Interestingly, several regions show very dense reciprocal connections with PVN BDNF neurons, including the lateral septum, the preoptic area, the ventromedial hypothalamic nucleus, the paraventricular thalamic nucleus, the zona incerta, the lateral parabrachial nucleus, the subiculum, the raphe magnus nucleus, and the raphe pallidus nucleus. These strong anatomical connections might be indicative of important functional connections. Therefore, we provide an outline of potential neural circuitry mediated by PVN BDNF neurons, which might be helpful to resolve the complex obesity network.