Journal
AGING CELL
Volume 14, Issue 6, Pages 1045-1054Publisher
WILEY
DOI: 10.1111/acel.12382
Keywords
aging; dwarf mice; growth hormone; hypothalamus; inflammation; longevity
Categories
Funding
- NIH [R01-AG019899]
- Ellison Medical Foundation
- UM Nathan Shock Center [P30-AG013283]
- Shock Center [AG-13283]
- Pepper Center [AG-024824]
- Michigan Diabetes Research Center [P30DK020572]
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Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-)) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived. Median longevity is also increased in mice with deletion of hypothalamic GH-releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6-week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR(-/-) mice lead to reduced formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18-month-old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF-1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF-1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early-life disruption of GH signaling produces longterm hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice.
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