Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice.
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 long-term hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice.
Department of Internal Medicine, Division of Geriatric and Palliative Medicine, University of Michigan, Ann Arbor, MI, USA.
Marianna
M
Sadagurski
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.
Taylor
T
Landeryou
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.
Gillian
G
Cady
Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
John J
JJ
Kopchick
Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
Edward O
EO
List
Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
Darlene E
DE
Berryman
Department of Internal Medicine-Geriatrics Research, Southern Illinois University School of Medicine, Springfield, IL, USA.
Andrzej
A
Bartke
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.
Richard A
RA
Miller
D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D004393:Dwarfism, Pituitary / Q000235:genetics* / Q000378:metabolism; D013006:Growth Hormone / Q000235:genetics / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D008297:Male; D020645:Mediodorsal Thalamic Nucleus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D002352:Carrier Proteins; D007328:Insulin; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C519530:insulin-like growth factor-1, mouse; D011333:Pro-Opiomelanocortin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C051815:somatotropin-binding protein
aging; dwarf mice; growth hormone; hypothalamus; inflammation; longevity