Abstract
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.
Highlights
Among genetically altered long-lived mice, animals with growth hormone (GH) deficiency, such as hypopituitary Ames and Snell dwarf mice, or GH insensitivity, such as the GH receptor (GHR) gene-disrupted mouse (GHRÀ/À), stand out by virtue of the magnitude of life extension and consistency of the findings across sexes, genetic background, and diets (Bartke & Brown-Borg, 2004; Bartke, 2008)
We evaluated three aspects of hypothalamic function in long-lived mice with GH and/or IGF-1 defects: (i) hypothalamic axonal projections; (ii) indices of inflammatory signals, each of which we had found to be altered in long-lived crowded litters (CL) mice; and (iii) responses to leptin injection
To determine whether GH-dependent pathway leads to alterations in hypothalamic axonal projections, we analyzed the immunoreactivity of agouti-related protein (AgRP)- and a-melanocyte-stimulating hormone (MSH)-containing fibers in three main hypothalamic projection areas: the arcuate nucleus of the hypothalamus (ARH), PVH, and DMH
Summary
Among genetically altered long-lived mice, animals with growth hormone (GH) deficiency, such as hypopituitary Ames (df/df) and Snell (dw/dw) dwarf mice, or GH insensitivity, such as the GH receptor (GHR) gene-disrupted mouse (GHRÀ/À), stand out by virtue of the magnitude of life extension and consistency of the findings across sexes, genetic background, and diets (Bartke & Brown-Borg, 2004; Bartke, 2008). These remarkably long-lived animals are characterized by reduced postnatal growth rate, delayed development, and reduced adult body size (Junnila et al, 2013). The majority of NPY mRNA-containing cells in the hypothalamic arcuate nucleus express the GHR gene, and NPY mRNA expression is downregulated in GHRÀ/À mice (Peng et al, 2001), suggesting that NPY neurons in the ARH mediate the feedback effect of GH on the hypothalamus
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