Stimulation of the hypothalamic ventromedial nuclei by pituitary adenylate cyclase-activating polypeptide induces hypophagia and thermogenesis

Numerous studies have demonstrated that the hypothalamic ventromedial nuclei (VMN) regulate energy homeostasis by integrating and utilizing behavioral and metabolic mechanisms. The VMN heavily express pituitary adenylate cyclase-activating polypeptide (PACAP) type I receptors (PAC1R). Despite the receptor distribution, most PACAP experiments investigating affects on feeding have focused on intracerebroventricular administration or global knockout mice. To identify the specific contribution of PACAP signaling in the VMN, we injected PACAP directly into the VMN and measured feeding behavior and indices of energy expenditure. Following an acute injection of PACAP, nocturnal food intake was significantly reduced for 6 h after injections without evidence of malaise. In addition, PACAP-induced suppression of feeding also occurred following an overnight fast and could be blocked by a specific PAC1R antagonist. Metabolically, VMN-specific injections of PACAP significantly increased both core body temperature and spontaneous locomotor activity with a concurrent increase in brown adipose uncoupling protein 1 mRNA expression. To determine which signaling pathways were responsive to PACAP administration into the VMN, we measured mRNA expression of well-characterized hypothalamic neuropeptide regulators of feeding. One hour after PACAP administration, expression of pro-opiomelanocortin mRNA was significantly increased in the arcuate nuclei (ARC), with no changes in neuropeptide Y and agouti-related polypeptide mRNA levels. This suggests that PAC1R expressing VMN neurons projecting to pro-opiomelanocortin neurons contribute to hypophagia by involving melanocortin signaling. While the VMN also abundantly express PACAP protein, the present study demonstrates that PACAP input to the VMN can influence the control of energy homeostasis.

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Feeding and Metabolism in Mice Lacking Pituitary Adenylate Cyclase-Activating Polypeptide

Endocrinology ◽

10.1210/en.2007-0515 ◽

2007 ◽

Vol 149 (4) ◽

pp. 1571-1580 ◽

Cited By ~ 39

Author(s):

Bruce A. Adams ◽

Sarah L. Gray ◽

Emma R. Isaac ◽

Antonio C. Bianco ◽

Antonio J. Vidal-Puig ◽

...

Keyword(s):

Food Intake ◽

Adenylate Cyclase ◽

Energy Homeostasis ◽

Tissue Type ◽

Mrna Levels ◽

Wild Type ◽

Reduced Body ◽

Hypothalamic Nuclei ◽

Brown Adipose ◽

Pituitary Adenylate Cyclase

Disruption of the pituitary adenylate cyclase-activating polypeptide (PACAP) gene in mice has demonstrated a role for this highly conserved neuropeptide in the regulation of metabolism and temperature control. Localization of PACAP neurons within hypothalamic nuclei that regulate appetite suggest PACAP may affect feeding and thus energy balance. We used PACAP-null mice to address this question, examining both food intake and energy expenditure. PACAP-null mice were leaner than wild-type littermates due to decreased adiposity and displayed increased insulin sensitivity. The lean phenotype in the PACAP-null mice was completely eliminated if animals were fed a high-fat diet or housed near thermoneutrality (28 C). Further metabolic analyses of PACAP-null mice housed at 21 C indicated that the reduced body weight could not be explained by decreased food intake, increased metabolic rate, or increased locomotor activity. The thyroid hormone axis of PACAP-null mice was affected, because mRNA levels of hypothalamic TRH and brown adipose tissue type 2 deiodinase were reduced in PACAP-null mice housed at room temperature, and brain deiodinase activity was lower in PACAP-null mice after an acute cold challenge compared with wild-type controls. These results demonstrate that PACAP is not required for the regulation of food intake yet is necessary to maintain normal energy homeostasis, likely playing a role in central cold-sensing mechanisms.

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Abstract 015: Regulation of Resting Metabolism by the Angiotensin AT 2 Receptor

Hypertension ◽

10.1161/hyp.64.suppl_1.015 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Nicole K Littlejohn ◽

Benjamin J Weidemann ◽

Nicole A Pearson ◽

Kathleen R Markan ◽

Matthew J Potthoff ◽

...

Keyword(s):

Energy Homeostasis ◽

Uncoupling Protein ◽

Resting Metabolic Rate ◽

Renin Angiotensin System ◽

Mrna Levels ◽

Interscapular Brown Adipose Tissue ◽

Normal Number ◽

Human Renin ◽

Brown Adipose ◽

Resting Metabolism

The renin-angiotensin system (RAS) positively correlates with obesity, and contributes to energy homeostasis through opposing actions in the brain and adipose. We hypothesize that site- and receptor-specific modulation may represent a novel therapeutic target for obesity. Transgenic “sRA” mice exhibit brain-specific RAS hyperactivity through expression of human renin in neurons (synapsin promoter) and human angiotensinogen via its own promoter. Previously we documented that sRA mice exhibit a suppressed circulating RAS, and an elevated resting metabolic rate (RMR) that is sensitive to replacement of circulating angiotensin II or the AT 2 receptor (AT 2 R) agonist, CGP-42112a (CGP, 100 ng/kg/min, s.c.). sRA mice consume more food than littermate controls (con n=7, 12.98±0.65 vs sRA n=8, 15.41±0.70 g/d, P<0.05), but because of a major suppression of digestive efficiency (con 77.6±2.3 vs sRA 59.3±4.7 % consumed, P<0.05), sRA mice absorb a normal number of calories (con 10.04±0.50 vs sRA 9.07±0.76 kcal/d). Chronic CGP had no effect on total daily caloric absorption (con+CGP n=7, 9.83±0.95 vs sRA+CGP n=5, 9.32±0.80 kcal/d); however CGP appears to disproportionately increase weight gain in sRA mice (vehicle +0.33±0.49 vs CGP +1.54±0.47 g/8 wks, P=0.27) compared to control mice (vehicle +2.12±1.00 vs CGP +2.47±0.73 g/8 wks, P=0.73), consistent with a suppression of energy expenditure by CGP. Given the increased RMR and core temperature in sRA mice, we next examined the expression of uncoupling protein-1 (UCP1) content of thermogenic adipose tissues by Western blot (all n=3, vs perilipin). Interscapular brown adipose tissue UCP1 was unchanged in sRA mice (94±6%), and weakly suppressed by CGP treatment (84±4% of sRA). Inguinal adipose UCP1 was increased in sRA mice (198±13%), and this was suppressed by CGP treatment (72±9% of sRA). UCP1 mRNA levels paralleled protein in both fat types. Cultured adipocytes from 4 day old AT 2 -deficient mice exhibited increased UCP1 protein vs littermate controls (190%). Further, CGP (10 nM) reduced UCP1 in control adipocytes (by 30%). These data support a suppressive action of AT 2 R upon RMR most likely through UCP1. Inguinal adipose AT 2 R may therefore contribute to obesity through suppression of RMR.

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Central stimulatory effect of leptin on T3production is mediated by brown adipose tissue type II deiodinase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00196.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. E980-E987 ◽

Cited By ~ 31

Author(s):

Philippe Cettour-Rose ◽

Albert G. Burger ◽

Christoph A. Meier ◽

Theo J. Visser ◽

Françoise Rohner-Jeanrenaud

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mrna Expression ◽

Uncoupling Protein ◽

Tissue Type ◽

Type I ◽

Type Ii ◽

Brown Adipose ◽

Small Doses ◽

Food Consumed

To assess whether intracerebroventricular leptin administration affects monodeiodinase type II (D2) activity in the tissues where it is expressed [cerebral cortex, hypothalamus, pituitary, and brown adipose tissue (BAT)], hepatic monodeiodinase type I (D1) activity was inhibited with propylthiouracil (PTU), and small doses of thyroxine (T4; 0.6 nmol · 100 g body wt−1 · day−1) were supplemented to compensate for the PTU-induced hypothyroidism. Two groups of rats were infused with leptin for 6 days, one of them being additionally treated with reverse triiodothyronine (rT3), an inhibitor of D2. Control rats were infused with vehicle and pair-fed the amount of food consumed by leptin-infused animals. Central leptin administration produced marked increases in D2 mRNA expression and activity in BAT, changes that were likely responsible for increased plasma T3 and decreased plasma T4 levels. Indeed, plasma T3 and T4 concentrations were unaltered by central leptin administration in the presence of rT3. The additional observation of a leptin-induced increased mRNA expression of BAT uncoupling protein-1 suggested that the effect on BAT D2 may be mediated by the sympathetic nervous system.

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Goldfish Calmodulin: Molecular Cloning, Tissue Distribution, and Regulation of Transcript Expression in Goldfish Pituitary Cells

Endocrinology ◽

10.1210/en.2004-0584 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5056-5067 ◽

Cited By ~ 13

Author(s):

Longfei Huo ◽

Eric K. Y. Lee ◽

P. C. Leung ◽

Anderson O. L. Wong

Keyword(s):

Amino Acid ◽

Adenylate Cyclase ◽

Mrna Expression ◽

Hormone Secretion ◽

Pituitary Hormone ◽

Pituitary Cells ◽

Mrna Levels ◽

Reading Frame ◽

Pituitary Adenylate Cyclase ◽

Neuroendocrine Mechanisms

Abstract Calmodulin (CaM) is a Ca2+-binding protein essential for biological functions mediated through Ca2+-dependent mechanisms. In the goldfish, CaM is involved in the signaling events mediating pituitary hormone secretion induced by hypothalamic factors. However, the structural identity of goldfish CaM has not been established, and the neuroendocrine mechanisms regulating CaM gene expression at the pituitary level are still unknown. Here we cloned the goldfish CaM and tested the hypothesis that pituitary expression of CaM transcripts can be the target of modulation by hypothalamic factors. Three goldfish CaM cDNAs, namely CaM-a, CaM-bS, and CaM-bL, were isolated by library screening. These cDNAs carry a 450-bp open reading frame encoding the same 149-amino acid CaM protein, the amino acid sequence of which is identical with that of mammals, birds, and amphibians and is highly homologous (≥90%) to that in invertebrates. In goldfish pituitary cells, activation of cAMP- or PKC-dependent pathways increased CaM mRNA levels, whereas the opposite was true for induction of Ca2+ entry. Basal levels of CaM mRNA was accentuated by GnRH and pituitary adenylate cyclase-activating polypeptide but suppressed by dopaminergic stimulation. Pharmacological studies using D1 and D2 analogs revealed that dopaminergic inhibition of CaM mRNA expression was mediated through pituitary D2 receptors. At the pituitary level, D2 activation was also effective in blocking GnRH- and pituitary adenylate cyclase-activating polypeptide-stimulated CaM mRNA expression. As a whole, the present study has confirmed that the molecular structure of CaM is highly conserved, and its mRNA expression at the pituitary level can be regulated by interactions among hypothalamic factors.

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Corticotropin-Releasing Hormone-Mediated Pathway of Leptin to Regulate Feeding, Adiposity, and Uncoupling Protein Expression in Mice

Endocrinology ◽

10.1210/en.2003-0301 ◽

2003 ◽

Vol 144 (8) ◽

pp. 3547-3554 ◽

Cited By ~ 57

Author(s):

Takayuki Masaki ◽

Go Yoshimichi ◽

Seiichi Chiba ◽

Tohru Yasuda ◽

Hitoshi Noguchi ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Food Intake ◽

Mrna Expression ◽

White Adipose Tissue ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Hypothalamic Nucleus ◽

Fat Cell ◽

Brown Adipose

Abstract To examine the functional role of CRH in the regulation of energy homeostasis by leptin, we measured the effects of the CRH antagonist, α-helical CRH 8–41 (αCRH) on a number of factors affected by leptin activity. These included food intake, body weight, hypothalamic c-fos-like immunoreactivity (c-FLI), weight and histological characterization of white adipose tissue, and mRNA expressions of uncoupling protein (UCP) in brown adipose tissue (BAT) in C57Bl/6 mice. Central infusion of leptin into the lateral cerebroventricle (icv) caused significant induction of c-FLI in the paraventricular nucleus (PVN), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus, and arcuate nucleus. In all these nuclei, the effect of leptin on expression of cFLI in the PVN and VMH was decreased by treatment with αCRH. Administration of leptin markedly decreased cumulative food intake and body weight with this effect being attenuated by pretreatment with αCRH. In peripheral tissue, leptin up-regulated BAT UCP1 mRNA expression and reduced fat depositions in this tissue. Those changes in BAT were also decreased by treatment with αCRH. As a consequence of the effects on food intake or energy expenditure, treatment with αCRH attenuated the leptin-induced reduction of body adiposity, fat cell size, triglyceride contents, and ob mRNA expression in white adipose tissue. Taken together, these results indicate that CRH neurons in the PVN and VMH may be an important mediator for leptin that contribute to regulation of feeding, adiposity, and UCP expression.

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Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase

Nutrients ◽

10.3390/nu13124204 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4204

Author(s):

Valentina Capelli ◽

Carmen Grijota-Martínez ◽

Nathalia R. V. Dragano ◽

Eval Rial-Pensado ◽

Johan Fernø ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Core Body Temperature ◽

Metabolic Effects ◽

Central Administration ◽

Treatment Protocols ◽

Brown Adipose ◽

Amp Activated Protein Kinase

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

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Progesterone increases mRNA levels of pituitary adenylate cyclase-activating polypeptide (PACAP) and type I PACAP receptor (PAC1) in the rat hypothalamus

Molecular Brain Research ◽

10.1016/s0169-328x(00)00070-x ◽

2000 ◽

Vol 78 (1-2) ◽

pp. 59-68 ◽

Cited By ~ 29

Author(s):

Chang Man Ha ◽

Ji Hyun Kang ◽

Eun Jung Choi ◽

Min Sung Kim ◽

Jeong-Woo Park ◽

...

Keyword(s):

Adenylate Cyclase ◽

Type I ◽

Mrna Levels ◽

Rat Hypothalamus ◽

Pituitary Adenylate Cyclase

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Food Intake and Core Body Temperature of Pups and Adults in a db Mouse Line Deficient in the Long Form of the Leptin Receptor without Misty Mutation

Journal of Diabetes Research ◽

10.1155/2018/9670871 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Wijang Pralampita Pulong ◽

Miharu Ushikai ◽

Emi Arimura ◽

Masaharu Abe ◽

Hiroaki Kawaguchi ◽

...

Keyword(s):

Food Intake ◽

Body Temperature ◽

Leptin Receptor ◽

Uncoupling Protein ◽

Core Body Temperature ◽

Mrna Levels ◽

Mouse Line ◽

Brown Adipose ◽

Long Form ◽

Core Body

Different involvement of leptin signaling in food intake (FI) and body temperature (BT) in pups and adults has been suggested. However, the leptin receptor (Lepr) long-form-deficient (db) mouse line has not been fully examined in pups. In the most available db mouse line, wild-type (WT) mice have a mutation in the dedicator of cytokinesis 7 gene, named misty, which was recently revealed to be involved in neuronal development. Therefore, we established a line of db mice without the misty mutation using natural mating. Adult (8 weeks of age) homozygous db/db mice displayed significantly higher core body weight (BW) and FI and significantly lower core BT than WT mice. However, postnatal (2 weeks of age) db/db mice displayed similar BW and milk intake and significantly lower core BT than WT mice. Correspondingly, adult and postnatal db/db mice exhibited altered mRNA levels of hypothalamic orexigenic and anorexigenic peptide in adults but not in pups. Additionally, db/db mice displayed significantly lower mRNA levels of brown adipose tissue uncoupling protein 1 at both ages. In conclusion, the db mouse line without the misty mutation clearly showed the different involvements of the Lepr long form in FI and BT in pups and adults.

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Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00293.2013 ◽

2013 ◽

Vol 305 (12) ◽

pp. E1452-E1463 ◽

Cited By ~ 28

Author(s):

Jon M. Resch ◽

Brian Maunze ◽

Adriana K. Gerhardt ◽

Samuel K. Magnuson ◽

Kailynn A. Phillips ◽

...

Keyword(s):

Adenylate Cyclase ◽

Energy Homeostasis ◽

Core Body Temperature ◽

Brain Regions ◽

Bed Nucleus ◽

Lateral Parabrachial Nucleus ◽

Pituitary Adenylate Cyclase ◽

Cholera Toxin Subunit B ◽

Cell Groups ◽

Core Body

Numerous studies have demonstrated that both the hypothalamic paraventricular nuclei (PVN) and ventromedial nuclei (VMN) regulate energy homeostasis through behavioral and metabolic mechanisms. Receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) are abundantly expressed in these nuclei, suggesting PACAP may be critical for the regulation of feeding behavior and body weight. To characterize the unique behavioral and physiological responses attributed to select hypothalamic cell groups, PACAP was site-specifically injected into the PVN or VMN. Overall food intake was significantly reduced by PACAP at both sites; however, meal pattern analysis revealed that only injections into the PVN produced significant reductions in meal size, duration, and total time spent eating. PACAP-mediated hypophagia in both the PVN and VMN was abolished by PAC1R antagonism, whereas pretreatment with a VPACR antagonist had no effect. PACAP injections into the VMN produced unique changes in metabolic parameters, including significant increases in core body temperature and spontaneous locomotor activity that was PAC1R dependent whereas, PVN injections of PACAP had no effect. Finally, PACAP-containing afferents were identified using the neuronal tracer cholera toxin subunit B (CTB) injected unilaterally into the PVN or VMN. CTB signal from PVN injections was colocalized with PACAP mRNA in the medial anterior bed nucleus of the stria terminalis, VMN, and lateral parabrachial nucleus (LPB), whereas CTB signal from VMN injections was highly colocalized with PACAP mRNA in the medial amygdala and LPB. These brain regions are known to influence energy homeostasis perhaps, in part, through PACAP projections to the PVN and VMN.

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