Dataset Information

A beta3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress.

ABSTRACT: Obesity has been associated with an increased risk of developing several psychiatric illnesses, including major depression and posttraumatic stress disorder. Likewise, these stress-related disturbances are associated with a higher rate of obesity; yet, the neurobiological mechanisms linking obesity and stress remain incompletely understood.Following exposure to chronic social defeat stress (CSDS), mice were given free access to either regular chow or a Western-style diet high in triglycerides and cholesterol. Comprehensive metabolic and behavioral testing was then conducted.Mice subjected to CSDS and then fed a high-fat diet for 30 days display severe behavioral deficits accompanied by redistribution of body fat. Stressed mice have decreased adipose tissue as well as decreased serum leptin levels compared with control mice. Pharmacological inhibition of beta(3)-adrenergic signaling during CSDS normalizes these metabolic abnormalities but worsens behavioral symptoms. Furthermore, mice subjected to CSDS display central leptin resistance including reduced expression of pro-opiomelanocortin in hypothalamus. Administration of a central melanocortin agonist worsens stress-induced behavioral deficits, while mice lacking the melanocortin-4 receptor display attenuated symptoms.These results indicate that chronic signaling through beta(3)-adrenergic receptors during social stress is an adaptive response that improves behavioral function. However, these responses come at the expense of central leptin resistance and melanocortin signaling alterations that contribute to significant and long-lasting metabolic abnormalities.

SUBMITTER: Chuang JC

PROVIDER: S-EPMC2868111 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A beta3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress.

Chuang Jen-Chieh JC Krishnan Vaishnav V Yu Hana G HG Mason Brittany B Cui Huxing H Wilkinson Matthew B MB Zigman Jeffrey M JM Elmquist Joel K JK Nestler Eric J EJ Lutter Michael M

Biological psychiatry 20100112 11

<h4>Background</h4>Obesity has been associated with an increased risk of developing several psychiatric illnesses, including major depression and posttraumatic stress disorder. Likewise, these stress-related disturbances are associated with a higher rate of obesity; yet, the neurobiological mechanisms linking obesity and stress remain incompletely understood.<h4>Methods</h4>Following exposure to chronic social defeat stress (CSDS), mice were given free access to either regular chow or a Western- ...[more]

PMID: 20060958

Similar Datasets

Project description:ObjectivePuberty is a key developmental phenomenon highly sensitive to metabolic modulation. Worrying trends of changes in the timing of puberty have been reported in humans. These might be linked to the escalating prevalence of childhood obesity and could have deleterious impacts on later (cardio-metabolic) health, but their underlying mechanisms remain unsolved. The neuropeptide α-MSH, made by POMC neurons, plays a key role in energy homeostasis by mediating the actions of leptin and likely participates in the control of reproduction. However, its role in the metabolic regulation of puberty and interplay with kisspeptin, an essential puberty-regulating neuropeptide encoded by Kiss1, remain largely unknown. We aim here to unveil the potential contribution of central α-MSH signaling in the metabolic control of puberty by addressing its role in mediating the pubertal effects of leptin and its potential interaction with kisspeptin.MethodsUsing wild type and genetically modified rodent models, we implemented pharmacological studies, expression analyses, electrophysiological recordings, and virogenetic approaches involving DREADD technology to selectively inhibit Kiss1 neurons, in order to interrogate the physiological role of a putative leptin→α-MSH→kisspeptin pathway in the metabolic control of puberty.ResultsStimulation of central α-MSH signaling robustly activated the reproductive axis in pubertal rats, whereas chronic inhibition of melanocortin receptors MC3/4R, delayed puberty, and prevented the permissive effect of leptin on puberty onset. Central blockade of MC3/4R or genetic elimination of kisspeptin receptors from POMC neurons did not affect kisspeptin effects. Conversely, congenital ablation of kisspeptin receptors or inducible, DREADD-mediated inhibition of arcuate nucleus (ARC) Kiss1 neurons resulted in markedly attenuated gonadotropic responses to MC3/4R activation. Furthermore, close appositions were observed between POMC fibers and ARC Kiss1 neurons while blockade of α-MSH signaling suppressed Kiss1 expression in the ARC of pubertal rats.ConclusionsOur physiological, virogenetic, and functional genomic studies document a novel α-MSH→kisspeptin→GnRH neuronal signaling pathway involved in transmitting the permissive effects of leptin on pubertal maturation, which is relevant for the metabolic (and, eventually, pharmacological) regulation of puberty onset.

Project description:BACKGROUND: Prevalence of obesity is increasing all over the world. ADRB3 Trp64Arg gene polymorphism was proposed to be associated with obesity, although inconsistent findings and differences of the Arg64 allele frequency among various ethnics were reported. Westernization was reported to increase the prevalence of obesity in developing world. In this study we determined the prevalence of obesity and metabolic syndrome among urban and rural Balinese, and studied the association of ADRB3 Trp64Arg polymorphism with obesity and MetS. FINDINGS: A total of 528 Balinese (urban 282, rural 246) were recruited. Body mass index (BMI) and waist circumference (WC) were determined; high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), systolic and diastolic blood pressure (SBP and DBP), and fasting plasma glucose (FPG) were measured using standard procedures. BMI and WC classifications were based on WHO classifications for Asian. Metabolic syndrome (MetS) was defined as described in the Joint Interim Statement. Chi-square test was employed to test the association between the ADRB3 Trp64Arg genotype and disease traits.Urban have higher BMI (p = 2.8 × 10-13), WC ( p < 2.2 × 10-16), TG (p = 0.0028), DBP (p = 1.8 × 10-5), and lower HDL-C (p = 0.0376) when compared to rural. Abdominal obesity and MetS prevalence were significantly higher in urban as compared to rural (both p < 0.001). The Arg64 allele frequency was similar between urban (0.06) and rural (0.05). The Arg64 rural female carriers have higher BMI and WC as compared to their Trp64 counterparts (p = 0.041 for BMI and p = 0.012 for WC), and consequently higher abdominal obesity prevalence (p = 0.007). Comparison between male and female, as well as urban and rural, showed different prevalence of MetS co-morbidities. Abdominal obesity and hypertriglyceridaemia were consistently appeared in all groups, suggesting to play a role as determinant of MetS in both urban and rural. CONCLUSIONS: Prevalence of obesity and MetS in urban were two times higher when compared to rural. Abdominal obesity and hypertriglyceridaemia appears to be the key determinant of MetS in both urban and rural Balinese. Our results indicated an association of the ADRB3 Trp64Arg gene polymorphism with obesity in the rural female.

Project description:Voiding dysfunctions, including increased voiding frequency, urgency, or incontinence, are prevalent in the postmenopausal population. Beta(3)-adrenergic receptor (beta(3)AR) agonists, which relax bladder smooth muscle, are being developed to treat these conditions. We utilized the rat ovariectomy (OVX) model to investigate the effect of ovarian hormone depletion on bladder function and the potential for beta(3)AR agonists to treat bladder hyperactivity in this setting. OVX increased voiding frequency and decreased bladder capacity by approximately 25% in awake rats and induced irregular cystometrograms in urethane-anesthetized rats. Reverse transcription-polymerase chain reaction revealed three betaARs subtypes (beta(1,2,3)) in bladder tissue, and immunostaining indicated beta(3)AR localization in urothelium and detrusor. Receptor expression was not different in OVX and SHAM rats. The beta(3)AR agonist selectivity of BRL37344 [(+/-)-(R(*),R(*))-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium hydrate], TAK-677 [(3-((2R)-(((2R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yloxy)acetic acid], and FK175 [acetic acid, 2-[[(8S)-8-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]oxy], ethyl ester, hydrochloride] was confirmed by examining the relative potency for elevation of cAMP in CHOK1 cells overexpressing the various rat betaARs. Intravenous injection of each of the beta(3)AR agonists (0.1-500 microg/kg) in anesthetized rats decreased voiding frequency, bladder pressure, and amplitude of bladder contractions. In bladder strips, beta(3)AR agonists (10(-12)-10(-4) M) decreased baseline tone and reduced spontaneous contractions. BRL37344 (5 mg/kg) and TAK-677 (5 mg/kg) injected intraperitoneally in awake rats decreased voiding frequency by 40 to 70%. These effects were not altered by OVX. The results indicate that OVX-induced bladder dysfunction, including decreased bladder capacity and increased voiding frequency, is not associated with changes in beta(3)AR expression or the bladder inhibitory effects of beta(3)AR agonists. This suggests that beta(3)AR agonists should prove effective for the treatment of overactive bladder symptoms in the postmenopausal population.

Dataset Information

A beta3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress.

Publications

A beta3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets