Age-associated gene expression changes in the arcuate nucleus of male rhesus macaques

The hypothalamic arcuate nucleus (ARC) represents a major component of the neuroendocrine reproductive axis and plays an important role in controlling the onset of puberty as well as age-associated reproductive senescence. Although significant gene expression changes have been observed in the ARC during sexual maturation, it is unclear what changes occur during aging, especially in males. Therefore, in the present study, we profiled the expression of reproduction-related genes in the ARC of young and old male rhesus macaques, as well as old males that had received 6 months of hormone supplementation (HS) in the form of daily testosterone and dehydroepiandrosterone; we also compared morning vs night ARC gene expression in the old males. Using Affymetrix gene microarrays, we found little evidence for age-associated expression changes for genes associated with the neuroendocrine reproductive axis, whereas using qRT-PCR, we detected a similar age-associated decrease in PGR (progesterone receptor) that we previously observed in postmenopausal females. We also detected a sex-steroid-dependent and age-associated decrease in androgen receptor (AR) expression, with highest AR levels being expressed at night (i.e., coinciding with the natural peak in daily testosterone secretion). Finally, unlike previous observations made in females, we did not find a significant age-associated increase in KISS1 (Kisspeptin) or TAC3 (Neurokinin B) expression in the ARC of males, most likely because the attenuation of circulating sex-steroid levels in the males was much less than that in postmenopausal females. Taken together, the data highlight some similarities and differences in ARC gene expression between aged male and female nonhuman primates.

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Lateral ventricular ghrelin and fourth ventricular ghrelin induce similar increases in food intake and patterns of hypothalamic gene expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00785.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. R1565-R1569 ◽

Cited By ~ 17

Author(s):

Kimberly P. Kinzig ◽

Karen A. Scott ◽

Jayson Hyun ◽

Sheng Bi ◽

Timothy H. Moran

Keyword(s):

Gene Expression ◽

Food Intake ◽

Fourth Ventricle ◽

Time Course ◽

Arcuate Nucleus ◽

Central Administration ◽

Stimulatory Action ◽

Hypothalamic Arcuate Nucleus ◽

Ghrelin Receptors ◽

The Brain

The gut peptide ghrelin has been shown to stimulate food intake after both peripheral and central administration, and the hypothalamic arcuate nucleus has been proposed to be the major site for mediating this feeding stimulatory action. Ghrelin receptors are widely distributed in the brain, and hindbrain ghrelin administration has been shown to potently stimulate feeding, suggesting that there may be other sites for ghrelin action. In the present study, we have further assessed potential sites for ghrelin action by comparing the ability of lateral and fourth ventricular ghrelin administration to stimulate food intake and alter patterns of hypothalamic gene expression. Ghrelin (0.32, 1, or 3.2 nmol) in the lateral or fourth ventricle significantly increased food intake in the first 4 h after injection, with no ventricle-dependent differences in degree or time course of hyperphagia. One nanomole of ghrelin into either the lateral or fourth ventricle resulted in similar increases in arcuate nucleus neuropeptide Y mRNA expression. Expression levels of agouti-related peptide or proopiomelanocortin mRNA were not affected by ghrelin administration. These data demonstrate that ghrelin can affect food intake and hypothalamic gene expression through interactions at multiple brain sites.

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Influence of photoperiod and gonadal status on food intake, adiposity, and gene expression of hypothalamic appetite regulators in a seasonal mammal

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00417.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R242-R252 ◽

Cited By ~ 19

Author(s):

Chantacha Anukulkitch ◽

Alexandra Rao ◽

Frank R. Dunshea ◽

Dominique Blache ◽

Gerald A. Lincoln ◽

...

Keyword(s):

Gene Expression ◽

Food Intake ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Reproductive Axis ◽

Pomc Gene ◽

Gonadal Status ◽

Long Photoperiod ◽

Refractory Phase

We studied the effects of photoperiod on metabolic profiles, adiposity, and gene expression of hypothalamic appetite-regulating peptides in gonad-intact and castrated Soay rams. Groups of five to six animals were studied 6, 18, or 30 wk after switching from long photoperiod (LP: 16 h of light) to short photoperiod (SP: 8 h of light). Reproductive and metabolic indexes were measured in blood plasma. Expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor (ObRb) in the arcuate nucleus was measured using in situ hybridization. Testosterone levels of intact animals were low under LP, increased to a peak at 16 wk under SP, and then declined. Voluntary food intake (VFI) was high under LP in both intact and castrated animals, decreased to a nadir at 12–16 wk under SP, and then recovered, but only in intact rams as the reproductive axis became photorefractory to SP. NPY gene expression varied positively and POMC expression varied negatively with the cycle in VFI, with differences between intact and castrate rams in the refractory phase. ObRb expression decreased under SP, unrelated to changes in VFI. Visceral fat weight also varied between the intact and castrated animals across the cycle. We conclude that 1) photoperiodic changes in VFI reflect changes in NPY and POMC gene expression, 2) changes in ObRb gene expression are not necessarily determinants of changes in VFI, 3) gonadal status affects the pattern of VFI that changes with photoperiod, and 4) in the absence of gonadal factors, animals can eat less but gain adiposity.

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Global transcriptome analysis of rat hypothalamic arcuate nucleus demonstrates reversal of hypothalamic gliosis following surgically and diet induced weight loss

Scientific Reports ◽

10.1038/s41598-019-52257-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Pernille Barkholt ◽

Kristoffer T. G. Rigbolt ◽

Mechthilde Falkenhahn ◽

Thomas Hübschle ◽

Uwe Schwahn ◽

...

Keyword(s):

Gene Expression ◽

Weight Loss ◽

Molecular Mechanisms ◽

Arcuate Nucleus ◽

Gene Expression Signature ◽

Global Gene Expression ◽

Metabolic Effects ◽

Expression Of Genes ◽

Hypothalamic Arcuate Nucleus ◽

Laser Capture

Abstract The central mechanisms underlying the marked beneficial metabolic effects of bariatric surgery are unclear. Here, we characterized global gene expression in the hypothalamic arcuate nucleus (Arc) in diet-induced obese (DIO) rats following Roux-en-Y gastric bypass (RYGB). 60 days post-RYGB, the Arc was isolated by laser-capture microdissection and global gene expression was assessed by RNA sequencing. RYGB lowered body weight and adiposity as compared to sham-operated DIO rats. Discrete transcriptome changes were observed in the Arc following RYGB, including differential expression of genes associated with inflammation and neuropeptide signaling. RYGB reduced gene expression of glial cell markers, including Gfap, Aif1 and Timp1, confirmed by a lower number of GFAP immunopositive astrocyte profiles in the Arc. Sham-operated weight-matched rats demonstrated a similar glial gene expression signature, suggesting that RYGB and dietary restriction have common effects on hypothalamic gliosis. Considering that RYGB surgery also led to increased orexigenic and decreased anorexigenic gene expression, this may signify increased hunger-associated signaling at the level of the Arc. Hence, induction of counterregulatory molecular mechanisms downstream from the Arc may play an important role in RYGB-induced weight loss.

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IMPACT OF MODERATE CALORIE RESTRICTION ON PITUITARY GENE EXPRESSION IN ADULT MALE RHESUS MACAQUES (Macaca mulatta)

Biology of Reproduction ◽

10.1093/biolreprod/77.s1.226 ◽

2007 ◽

Vol 77 (Suppl_1) ◽

pp. 226-226

Author(s):

Brandon Sitzmann ◽

Julie Mattison ◽

Donald Ingram ◽

George Roth ◽

Mary Ann Ottinger ◽

...

Keyword(s):

Gene Expression ◽

Calorie Restriction ◽

Adult Male ◽

Macaca Mulatta ◽

Rhesus Macaques ◽

Male Rhesus

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Increased Neurokinin B (Tac2) Expression in the Mouse Arcuate Nucleus Is an Early Marker of Pubertal Onset with Differential Sensitivity to Sex Steroid-Negative Feedback than Kiss1

Endocrinology ◽

10.1210/en.2012-1529 ◽

2012 ◽

Vol 153 (10) ◽

pp. 4883-4893 ◽

Cited By ~ 41

Author(s):

John C. Gill ◽

Víctor M. Navarro ◽

Cecilia Kwong ◽

Sekoni D. Noel ◽

Cecilia Martin ◽

...

Keyword(s):

Negative Feedback ◽

Arcuate Nucleus ◽

Pubertal Development ◽

Differential Sensitivity ◽

Sex Steroid ◽

Wild Type ◽

Neurokinin B ◽

Pubertal Onset ◽

Steroid Dependent

Abstract At puberty, neurokinin B (NKB) and kisspeptin (Kiss1) may help to amplify GnRH secretion, but their precise roles remain ambiguous. We tested the hypothesis that NKB and Kiss1 are induced as a function of pubertal development, independently of the prevailing sex steroid milieu. We found that levels of Kiss1 mRNA in the arcuate nucleus (ARC) are increased prior to the age of puberty in GnRH/sex steroid-deficient hpg mice, yet levels of Kiss1 mRNA in wild-type mice remained constant, suggesting that sex steroids exert a negative feedback effect on Kiss1 expression early in development and across puberty. In contrast, levels of Tac2 mRNA, encoding NKB, and its receptor (NK3R; encoded by Tacr3) increased as a function of puberty in both wild-type and hpg mice, suggesting that during development Tac2 is less sensitive to sex steroid-dependent negative feedback than Kiss1. To compare the relative responsiveness of Tac2 and Kiss1 to the negative feedback effects of gonadal steroids, we examined the effect of estradiol (E2) on Tac2 and Kiss1 mRNA and found that Kiss1 gene expression was more sensitive than Tac2 to E2-induced inhibition at both juvenile and adult ages. This differential estrogen sensitivity was tested in vivo by the administration of E2. Low levels of E2 significantly suppressed Kiss1 expression in the ARC, whereas Tac2 suppression required higher E2 levels, supporting differential sensitivity to E2. Finally, to determine whether inhibition of NKB/NK3R signaling would block the onset of puberty, we administered an NK3R antagonist to prepubertal (before postnatal d 30) females and found no effect on markers of pubertal onset in either WT or hpg mice. These results indicate that the expression of Tac2 and Tacr3 in the ARC are markers of pubertal activation but that increased NKB/NK3R signaling alone is insufficient to trigger the onset of puberty in the mouse.

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Altered Gene Expression Profiles of the Hypothalamic Arcuate Nucleus of Male Mice Suggest Profound Developmental Changes in Peptidergic Signaling

Neuroendocrinology ◽

10.1159/000439430 ◽

2015 ◽

Vol 103 (3-4) ◽

pp. 369-382 ◽

Cited By ~ 7

Author(s):

Csilla S. Molnár ◽

Miklós Sárvári ◽

Csaba Vastagh ◽

Csilla Maurnyi ◽

Csaba Fekete ◽

...

Keyword(s):

Gene Expression ◽

Arcuate Nucleus ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Developmental Changes ◽

Male Mice ◽

Altered Gene Expression ◽

Hypothalamic Arcuate Nucleus ◽

Altered Gene

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Regulation of leptin receptor, POMC and AGRP gene expression by photoperiod and food deprivation in the hypothalamic arcuate nucleus of the male Siberian hamster (Phodopus sungorus)

Appetite ◽

10.1006/appe.1999.0301 ◽

2000 ◽

Vol 34 (1) ◽

pp. 109-111 ◽

Cited By ~ 22

Author(s):

JG Mercer ◽

KM Moar ◽

AW Ross ◽

PJ Morgan

Keyword(s):

Gene Expression ◽

Food Deprivation ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Phodopus Sungorus ◽

Siberian Hamster ◽

Hypothalamic Arcuate Nucleus

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Photoperiod regulates arcuate nucleus POMC, AGRP, and leptin receptor mRNA in Siberian hamster hypothalamus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.1.r271 ◽

2000 ◽

Vol 278 (1) ◽

pp. R271-R281 ◽

Cited By ~ 66

Author(s):

Julian G. Mercer ◽

Kim M. Moar ◽

Alexander W. Ross ◽

Nigel Hoggard ◽

Peter J. Morgan

Keyword(s):

Gene Expression ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Separate Experiment ◽

Siberian Hamsters ◽

Hypothalamic Arcuate Nucleus ◽

Melanin Concentrating Hormone ◽

Specific Regulation ◽

Plasma Leptin ◽

Agouti Related Protein

Siberian hamsters decreased body weight by 30% during 18 wk in short day (SD) vs. long day (LD) controls. Subsequent imposed food deprivation (FD; 24 h) caused a further 10% decrease. In the hypothalamic arcuate nucleus (ARC), SDs reduced proopiomelanocortin (POMC) gene expression and agouti-related protein (AGRP) mRNA was elevated, changes that summate to reduced catabolic drive through the melanocortin receptors. There was no effect of photoperiod on neuropeptide Y (NPY), melanin concentrating hormone, orexin, or corticotropin-releasing factor mRNAs. Superimposed FD increased AGRP gene expression and caused a localized elevation of NPY mRNA in the ARC. Both adipose tissue leptin and ARC leptin receptor (OB-Rb) mRNAs were downregulated in SDs, whereas FD increased OB-Rb gene expression. Thus OB-Rb mRNA is differentially regulated by acute and chronic changes in plasma leptin in this species. In a separate experiment in LDs, AGRP gene expression was increased by 24 or 48 h FD, whereas POMC mRNA was downregulated in the caudal ARC. AGRP and NPY mRNAs were extensively coexpressed in the ARC, and their differential regulation by photoperiod and FD is suggestive of transcript-specific regulation at the level of individual neurons.

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