Dataset Information

Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21.

ABSTRACT: TLQP-21, a peptide encoded by the highly conserved vgf gene, is expressed in neuroendocrine cells and has been the most prominent VGF-derived peptide studied in relation to control of energy balance. The recent discovery that TLQP-21 is the natural agonist for the complement 3a receptor 1 (C3aR1) has revived interest in this peptide as a potential drug target for obesity. We have investigated its function in Siberian hamsters (Phodopus sungorus), a rodent that displays natural seasonal changes in body weight and adiposity as an adaptation to survive winter. We have previously shown that intracerebroventricular administration of TLQP-21 reduced food intake and body weight in hamsters in their long-day fat state. The aim of our current study was to determine the systemic actions of TLQP-21 on food intake, energy expenditure and body weight, and to establish whether adiposity affected these responses. Peripheral infusion of TLQP-21 (1mg/kg/day for 7 days) in lean hamsters exposed to short photoperiods (SP) reduced cumulative food intake in the home cage (p<0.05), and intake when measured in metabolic cages (P<0.01). Energy expenditure was significantly increased (p<0.001) by TLQP-21 infusion, this was associated with a significant increase in uncoupling protein 1 mRNA in brown adipose tissue (BAT) (p<0.05), and body weight was significantly reduced (p<0.05). These effects of systemic TLQP-21 treatment were not observed in hamsters exposed to long photoperiod (LP) with a fat phenotype. C3aR1 mRNA and protein were abundantly expressed in the hypothalamus, brown and white adipose tissue in hamsters, but changes in expression cannot explain the differential response to TLQP-21 in lean and fat hamsters.

SUBMITTER: Lisci C

PROVIDER: S-EPMC6715173 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21.

Lisci Carlo C Lewis Jo E JE Daniel Zoe C T R ZCTR Stevenson Tyler J TJ Monnier Chloe C Marshall Hayley J HJ Fowler Maxine M Ebling Francis J P FJP Ferri Gian-Luca GL Ferri Gian-Luca GL Cocco Cristina C Jethwa Preeti H PH

PloS one 20190829 8

TLQP-21, a peptide encoded by the highly conserved vgf gene, is expressed in neuroendocrine cells and has been the most prominent VGF-derived peptide studied in relation to control of energy balance. The recent discovery that TLQP-21 is the natural agonist for the complement 3a receptor 1 (C3aR1) has revived interest in this peptide as a potential drug target for obesity. We have investigated its function in Siberian hamsters (Phodopus sungorus), a rodent that displays natural seasonal changes i ...[more]

PMID: 31465472

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Project description:BackgroundMultiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) identified VGF as a major driver of Alzheimer's disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression.MethodsWe performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human.ResultsWe demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA- and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21.ConclusionsThese data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.

Project description:Seasonally breeding animals exhibit profound physiological and behavioural responses to changes in ambient day length (photoperiod), including changes in reproductive function and territorial aggression.Species where aggression persists when gonads are regressed and circulating levels of gonadal hormones are low, such as Siberian hamsters (Phodopus sungorus) and song sparrows (Melospiza melodia), challenge the well-established framework that gonadal hormones are important mediators of aggression.A solution to this apparent paradox is that a season-specific increase in sensitivity to hormones in brain areas associated with aggression offsets low levels of gonadal hormones during periods of reproductive quiescence.To test this hypothesis, we manipulated photoperiod to induce natural fluctuations in seasonal phenotype across multiple stages of the annual reproductive cycle in female Siberian hamsters that display increased aggression during short-day reproductive quiescence, suggesting that behaviour persists independent of gonadal steroids.Females were housed in long "summer" days or short "winter" days for 10, 24 or 30 weeks to capture gonadal regression, transition back to a reproductively functional state and full gonadal recrudescence, respectively.Long-day animals maintained reproductive functionality and displayed low aggression across all time points. By week 10, short-day reproductively responsive females underwent gonadal regression and displayed increased aggression; non-responsive animals showed no such changes. At week 24, animals were in a transitional period and displayed an intermediate phenotype with respect to reproduction and aggression. By week 30, short-day females were fully recrudesced and returned to long-day-like levels of aggression.Consistent with our hypothesis, gonadally regressed females displayed decreases in 17β-oestradiol (oestradiol) levels, but site-specific increases in the abundance of brain oestrogen receptor-alpha (ERα) in regions associated with aggression, but not reproduction. Increased site-specific ERα may function as a compensatory mechanism to allow increased responsiveness to oestradiol in regulating aggression in lieu of high circulating concentrations of hormones.Collectively, these results broaden our understanding of how breeding phenology maps onto social behaviour and the mechanisms that have evolved to coordinate behaviours that occur in non-breeding contexts.

Project description:Siberian hamsters (Phodopus sungorus) adapt to seasonal environmental conditions with marked changes in body mass, primarily in the form of adiposity. Winter-like conditions (e.g. short days) are sufficient to decrease body mass by approximately 30% in part via reductions in food intake. The neuroendocrine mechanisms responsible for these changes are not well understood, and homeostatic orexigenic/anorexigenic systems of the hypothalamus provide little explanation. We investigated the potential role of endocannabinoids, which are known modulators of appetite and metabolism, in mediating seasonal changes in energy balance. Specifically, we housed hamsters in long or short days for 0, 3, or 9 weeks and measured endocannabinoid levels in the hypothalamus, brainstem, liver and retroperitoneal white adipose tissue (RWAT). An additional group of males housed in short days for 25 weeks were also compared with long-day controls. Following 9 weeks in short days, levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) were significantly elevated in RWAT and reduced in brainstem, although they returned to long-day levels by week 25 in short-day males that had cycled back to summer-like energy balance. Endocannabinoid levels in these tissues correlated significantly with adiposity and change in body mass. No photoperiodic changes were observed in the hypothalamus or liver; however, sex differences in 2-AG levels were found in the liver (males > females). We further tested the effects of CB(1) receptor signalling on ingestive behaviour. Five daily injections of CB(1) antagonist SR141716 significantly reduced food intake and body mass but not food hoarding. Although the CB(1) agonist arachidonyl-2-chloroethylamide did not appreciably affect either ingestive behaviour, body mass was significantly elevated following 2 days of injections. Taken altogether, these findings demonstrate that endocannabinoid levels vary with sex and photoperiod in a site-specific manner, and that altered signalling at CB(1) receptors affects energy balance in Siberian hamsters.

Dataset Information

Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21.

Publications

Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21.

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