Transient early food restriction leads to hypothalamic changes in the long‐lived crowded litter female mice

Physiological Reports

Marianna Sadagurski³  Taylor Landeryou²  Gillian Cady²  Andrzej Bartke⁴  Ernesto Bernal-Mizrachi¹ 

[1]Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

[2]Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan

[3]Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

[4]Department of Internal Medicine–Geriatrics Research, Southern Illinois University School of Medicine, Springfield, Illinois

关键词: Aging;    caloric restriction;    hypothalamus;    metabolism;   

DOI  :  10.14814/phy2.12379

来源: Wiley

【 摘 要 】

Abstract

Transient nutrient restriction in the 3 weeks between birth and weaning (producing “crowded litter” or CL mice) leads to a significant increase in lifespan and is associated with permanent changes in energy homeostasis, leptin, and insulin sensitivity. Here, we show this brief period of early food restriction leads to permanent modulation of the arcuate nucleus of the hypothalamus (ARH), markedly increasing formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the paraventricular nucleus of the hypothalamus (PVH). An additional 4 weeks of caloric restriction, after weaning, does not further intensify the formation of AgRP and POMC projections. Acute leptin stimulation of 12-month-old mice leads to a stronger increase in the levels of hypothalamic pStat3 and cFos activity in CL mice than in controls, suggesting that preweaning food restriction leads to long-lasting enhancement of leptin signaling. In contrast, FoxO1 nuclear exclusion in response to insulin is equivalent in young adult CL and control mice, suggesting that hypothalamic insulin signaling is not modulated by the crowded litter intervention. Markers of hypothalamic reactive gliosis associated with aging, such as Iba1-positive microglia and GFAP-positive astrocytes, are significantly reduced in CL mice as compared to controls at 12 and 22 months of age. Lastly, age-associated overproduction of TNF-α in microglial cells is reduced in CL mice than in age-matched controls. Together, these results suggest that transient early life nutrient deprivation leads to long-term hypothalamic changes which may contribute to the longevity of CL mice.

【 授权许可】

CC BY   
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.