Early-Life Exposure to Testosterone Programs the Hypothalamic Melanocortin System

Abstract In mammals, males consume more food, which is considered a masculinized behavior, but the underlying mechanism of this sex-specific feeding behavior is unknown. In mice, neonatal testosterone (NT) is critical to masculinize the developing brain, leading to sex differences in reproductive physiology. The proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) are critical to suppress energy intake and POMC innervation of hypothalamic feeding circuits develops to a large extent neonatally. We hypothesized that NT programs the masculinization of energy intake by programming POMC neurons. We tested this hypothesis by comparing control females and control males (CMs) with female mice neonatally androgenized with testosterone (NTFs). We show that increased food intake in CMs is associated with reduced POMC expression and decreased intensity of neuronal projections from POMC neurons within the ARC compared with control females. We found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT). NTFs also exhibit hyperleptinemia and a decreased ability of leptin to up-regulate POMC, suppress food intake, and prevent adipose tissue accumulation, independent of signal transducer and activator of transcription 3. However, this leptin resistance is specific to NTFs, is not a consequence of masculinization, and is reproduced by neonatal exposure to estrogen but not DHT. Thus, NT programs a sexual differentiation of POMC neurons in female mice via DHT but also predisposes to leptin resistance and obesity in an estrogen-dependent manner.

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Involvement of the Acyl-CoA binding domain containing 7 in the control of food intake and energy expenditure in mice

eLife ◽

10.7554/elife.11742 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 12

Author(s):

Damien Lanfray ◽

Alexandre Caron ◽

Marie-Claude Roy ◽

Mathieu Laplante ◽

Fabrice Morin ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Arcuate Nucleus ◽

Binding Domain ◽

Nucleotide Polymorphism ◽

Melanocortin System ◽

Single Nucleotide ◽

Hypothalamic Arcuate Nucleus ◽

Paralog Gene ◽

G Protein Coupled

Acyl-CoA binding domain-containing 7 (Acbd7) is a paralog gene of the diazepam-binding inhibitor/Acyl-CoA binding protein in which single nucleotide polymorphism has recently been associated with obesity in humans. In this report, we provide converging evidence indicating that a splice variant isoform of the Acbd7 mRNA is expressed and translated by some POMC and GABAergic-neurons in the hypothalamic arcuate nucleus (ARC). We have demonstrated that the ARC ACBD7 isoform was produced and processed into a bioactive peptide referred to as nonadecaneuropeptide (NDN) in response to catabolic signals. We have characterized NDN as a potent anorexigenic signal acting through an uncharacterized endozepine G protein-coupled receptor and subsequently via the melanocortin system. Our results suggest that ACBD7-producing neurons participate in the hypothalamic leptin signalling pathway. Taken together, these data suggest that ACBD7-producing neurons are involved in the hypothalamic control exerted on food intake and energy expenditure by the leptin-melanocortin pathway.

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Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance

Journal of Endocrinology ◽

10.1677/joe-06-0074 ◽

2007 ◽

Vol 192 (2) ◽

pp. 271-278 ◽

Cited By ~ 25

Author(s):

Elżbieta Król ◽

John R Speakman

Keyword(s):

Food Intake ◽

Body Mass ◽

Arcuate Nucleus ◽

Leptin Resistance ◽

Microtus Agrestis ◽

Loss Of Control ◽

Digestive Efficiency ◽

Leptin Sensitivity ◽

Efficiency Measures ◽

Hypothalamic Arcuate Nucleus

Adult mammals are typically highly resistant to perturbations in their energy balance. In obese humans, however, this control appears to be lost. Apart from a few exceptional cases, this loss of control occurs despite appropriate levels of circulating leptin – suggesting that elevated adiposity may be a consequence of failure to respond to the leptin signal: leptin resistance. When cold-acclimated male field voles (Microtus agrestis) are transferred from short (SD, 8 h light) to long (LD, 16 h light) photoperiods, they increase dramatically in body mass and fatness for about 4 weeks. After this period, their mass stabilizes at a new plateau about 25% higher than animals maintained in SD. The increase in adiposity is not caused by significant increases in food intake, but reflects an increase in digestive efficiency. Measures of circulating leptin reveal that the increased adiposity is matched by increased circulating leptin. By infusing voles with exogenous leptin, we have demonstrated that SD voles are leptin sensitive (reducing both body mass and food intake), whereas LD animals are leptin resistant. Voles may therefore be a useful model for understanding the process of leptin resistance. The change in leptin sensitivity in voles was not associated with changes in the levels of gene expression of the orexogenic or anorexogenic neuropeptides, such as neuropeptide Y, agouti-related peptide, POMC and cocaine- and amphetamine-regulated transcript, measured in the hypothalamic arcuate nucleus (ARC). During the phase that body mass was increasing, however, there was a transient increase in the ARC expression of suppressor of cytokine signalling-3 (SOCS3). These data suggest that the changes in the expression of SOCS3 in the ARC may be involved in leptin resistance. However, the mechanism by which these changes may be linked to alterations in digestive efficiency that underpin the changes in adiposity, or how the differences are signalled by changes in photoperiod, remains unclear.

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Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation

International Journal of Molecular Sciences ◽

10.3390/ijms19082333 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2333 ◽

Cited By ~ 8

Author(s):

Yi-Heng Lee ◽

Hao-Chieh Hsu ◽

Pei-Chen Kao ◽

Young-Ji Shiao ◽

Skye Hsin-Hsien Yeh ◽

...

Keyword(s):

Food Intake ◽

Transgenic Mice ◽

High Fat Diet ◽

Energy Homeostasis ◽

Underlying Mechanism ◽

Leptin Resistance ◽

High Fat ◽

Interscapular Brown Adipose Tissue ◽

Positron Emission ◽

Brown Adipose

Alzheimer’s disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aβ and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis.

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Consuming sucrose solution promotes leptin resistance and site specifically modifies hypothalamic leptin signaling in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00238.2020 ◽

2020 ◽

Author(s):

Ruth B.S. Harris

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Energy Intake ◽

Sucrose Solution ◽

Ventromedial Hypothalamus ◽

Primary Response ◽

Leptin Resistance ◽

Sprague Dawley ◽

Leptin Signaling ◽

Transient Rise

Rats consuming 30% sucrose solution and a sucrose-free diet (LiqS) become leptin resistant whereas rats consuming sucrose from a formulated diet (HS) remain leptin responsive. This study tested whether leptin resistance in LiqS rats extended beyond a failure to inhibit food intake and examined leptin responsiveness in the hypothalamus and hindbrain of rats offered HS, LiqS or a sucrose free diet (NS). Female LiqS Sprague Dawley rats initially only partially compensated for the calories consumed as sucrose, but energy intake matched that of HS and NS rats when they were transferred to calorimetry cages. There was no effect of diet on energy expenditure, IBAT temperature or fat pad weight. A peripheral injection of 2 mg leptin/kg on Day 23 or 26 inhibited energy intake of HS and NS, but not LiqS rats. Inhibition occurred earlier in HS than NS rats and was associated with a smaller meal size. Leptin had no effect on energy expenditure, but caused a transient rise in IBAT temperature of HS rats. Leptin increased pSTAT3 in the hindbrain and ventromedial hypothalamus of all rats. There was a minimal effect of leptin in the arcuate nucleus and only the dorsomedial hypothalamus showed a correlation between pSTAT3 and leptin responsiveness. These data suggest that the primary response to leptin is inhibition of food intake and that the pattern of sucrose consumption, rather than calories consumed as sucrose causes leptin resistance associated with site specific differences in hypothalamic leptin signaling.

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Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats

Journal of Endocrinology ◽

10.1530/joe-15-0519 ◽

2016 ◽

Vol 229 (2) ◽

pp. 85-96 ◽

Cited By ~ 12

Author(s):

Martina Holubová ◽

Jana Zemenová ◽

Barbora Mikulášková ◽

Vladimíra Panajotova ◽

Jiří Stöhr ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Glucose Tolerance ◽

Leptin Receptor ◽

Leptin Resistance ◽

Dependent Manner ◽

Sprague Dawley ◽

Obesity And Diabetes ◽

Diabetes Diet ◽

Zdf Rats

Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood–brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of bothPrrp-knockout andPrrpreceptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague–Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.

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Melanocortin activity in the amygdala controls appetite for dietary fat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00591.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. R385-R393 ◽

Cited By ~ 41

Author(s):

Stéphane Boghossian ◽

MieJung Park ◽

David A. York

Keyword(s):

Food Intake ◽

Dietary Fat ◽

Central Nucleus ◽

Calorie Intake ◽

Dependent Manner ◽

Sprague Dawley ◽

Melanocortin System ◽

Total Calorie ◽

Dose Dependent ◽

Total Calorie Intake

The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total calorie intake (−35.5% after 24 h, P < 0.05). Total calorie intake increased in both AgRP- and SHU-9119-treated rats (32 and 109% after 24 h, respectively) as the result of increased intake of HF diet. There was no modification of LF consumption with AgRP treatment and a transient nonsignificant decrease with SHU-9119 treatment. Amygdala brain-derived neurotrophic factor expression was increased by AgRP in fed rats. These results identify the amygdala as a site of action for the melanocortin system to control food intake and dietary preferences.

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VTA MC3R neurons control feeding in an activity and sex-dependent manner in mice

10.1101/2021.03.09.434586 ◽

2021 ◽

Author(s):

Anna I. Dunigan ◽

David P. Olson ◽

Aaron G. Roseberry

Keyword(s):

Body Weight ◽

Sex Differences ◽

Tyrosine Hydroxylase ◽

Food Intake ◽

Ventral Tegmental Area ◽

Neuronal Activity ◽

Dependent Manner ◽

Male And Female ◽

Female Mice

AbstractIncreasing evidence indicates that the melanocortin and mesolimbic dopamine systems interact to regulate feeding and body weight. Because melanocortin-3 receptors (MC3R) are highly expressed in the ventral tegmental area (VTA), we tested whether VTA neurons expressing these receptors (VTA MC3R neurons) control feeding and body weight in vivo. We also tested whether there were sex differences in the ability of VTA MC3R neurons to control feeding, as MC3R −/− mice show sex-dependent alterations in reward feeding and dopamine levels, and there are clear sex differences in multiple dopamine-dependent behaviors and disorders. DREADD receptors were used to acutely activate and inhibit VTA MC3R neurons and changes in food intake and body weight were measured. Acutely altering the activity of VTA MC3R neurons decreased feeding in an activity- and sex-dependent manner, with acute activation decreasing feeding, but only in females, and acute inhibition decreasing feeding, but only in males. These differences did not appear to be due to sex differences in the number of VTA MC3R neurons, the ability of hM3Dq to activate VTA MC3R neurons, or the proportion of VTA MC3R neurons expressing tyrosine hydroxylase (TH). These studies demonstrate an important role for VTA MC3R neurons in the control of feeding and reveal important sex differences in behavior, whereby opposing changes in neuronal activity in male and female mice cause similar changes in behavior.

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The feeding microstructure of male and female mice

PLoS ONE ◽

10.1371/journal.pone.0246569 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0246569

Author(s):

Yakshkumar Dilipbhai Rathod ◽

Mauricio Di Fulvio

Keyword(s):

Energy Balance ◽

Energy Intake ◽

Negative Energy ◽

Meal Size ◽

Negative Energy Balance ◽

Dependent Manner ◽

Eating Time ◽

Male And Female ◽

Female Mice ◽

Old Females

The feeding pattern and control of energy intake in mice housed in groups are poorly understood. Here, we determined and quantified the normal feeding microstructure of social male and female mice of the C57BL/6J genetic background fed a chow diet. Mice at 10w, 20w and 30w of age showed the expected increase in lean and fat mass, being the latter more pronounced and variable in males than in females. Under ad libitum conditions, 20w and 30w old females housed in groups showed significantly increased daily energy intake when adjusted to body weight relative to age-matched males. This was the combined result of small increases in energy intake during the nocturnal and diurnal photoperiods of the day without major changes in the circadian pattern of energy intake or spontaneous ambulatory activity. The analysis of the feeding microstructure suggests sex- and age-related contributions of meal size, meal frequency and intermeal interval to the control of energy intake under stable energy balance, but not under negative energy balance imposed by prolonged fasting. During the night, 10-20w old females ate less frequently bigger meals and spent more time eating them resulting in reduced net energy intake relative to age-matched males. In addition, male and female mice at all ages tested significantly shortened the intermeal interval during the first hours of re-feeding in response to fasting without affecting meal size. Further, 20-30w old males lengthened their intermeal interval as re-feeding time increased to reach fed-levels faster than age-matched females. Collectively, our results suggest that the physiological mechanisms controlling meal size (satiation) and the non-eating time spent between meals (satiety) during stable or negative energy balance are regulated in a sex- and age-dependent manner in social mice.

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Early Life Exposure to Antibiotic Alters Energy Balance during Chronic High-Fat Feeding in Adult Male and Female Mice

Diabetes ◽

10.2337/db18-1999-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1999-P ◽

Cited By ~ 1

Author(s):

HYE LIM NOH ◽

SUJIN SUK ◽

RANDALL H. FRIEDLINE ◽

KUNIKAZU INASHIMA ◽

DUY A. TRAN ◽

...

Keyword(s):

Energy Balance ◽

Adult Male ◽

Early Life ◽

High Fat ◽

Male And Female ◽

Female Mice ◽

Early Life Exposure ◽

Fat Feeding

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Effect of ultraprocessed food intake on cardiometabolic risk is mediated by diet quality: a cross-sectional study

BMJ Nutrition, Prevention & Health ◽

10.1136/bmjnph-2020-000225 ◽

2021 ◽

pp. bmjnph-2020-000225

Author(s):

Jennifer Griffin ◽

Anwar Albaloul ◽

Alexandra Kopytek ◽

Paul Elliott ◽

Gary Frost

Keyword(s):

Food Intake ◽

Energy Intake ◽

Food Consumption ◽

Outcome Measures ◽

Diet Quality ◽

Cardiometabolic Risk ◽

Saturated Fat ◽

Secondary Outcome ◽

Cross Sectional ◽

Occupational Cohort

ObjectiveTo examine the effect of the consumption of ultraprocessed food on diet quality, and cardiometabolic risk (CMR) in an occupational cohort.DesignCross-sectional.SettingOccupational cohort.Participants53 163 British police force employees enrolled (2004–2012) into the Airwave Health Monitoring Study. A total of 28 forces across the UK agreed to participate. 9009 participants with available 7-day diet record data and complete co-variate data are reported in this study.Main outcome measuresA CMR and Dietary Approaches to Stop Hypertension score were treated as continuous variables and used to generate measures of cardiometabolic health and diet quality. Secondary outcome measures include percentage of energy from fat, saturated fat, carbohydrate, protein and non-milk extrinsic sugars (NMES) and fibre grams per 1000 kcal of energy intake.ResultsIn this cohort, 58.3%±11.6 of total energy intake was derived from ultraprocessed (NOVA 4) foods. Ultraprocessed food intake was negatively correlated with diet quality (r=−0.32, p<0.001), fibre (r=−0.20, p<0.001) and protein (r = −0.40, p<0.001) and positively correlated with fat (r=0.18, p<0.001), saturated fat (r=0.14, p<0.001) and nmes (r=0.10, p<0.001) intake . Multivariable analysis suggests a positive association between ultraprocessed food (NOVA 4) consumption and CMR. However, this main effect was no longer observed after adjustment for diet quality (p=0.209). Findings from mediation analysis indicate that the effect of ultraprocessed food (NOVA 4) intake on CMR is mediated by diet quality (p<0.001).ConclusionsUltraprocessed food consumption is associated with a deterioration in diet quality and positively associated with CMR, although this association is mediated by and dependent on the quality of the diet. The negative impact of ultraprocessed food consumption on diet quality needs to be addressed and controlled studies are needed to fully comprehend whether the relationship between ultraprocessed food consumption and health is independent to its relationship with poor diet quality.

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