Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high fat diet-related insulin resistance, steatosis and adipose dysfunction

ABSTRACT Objective Differences in primate and non-primate growth hormone (GH) genes can affect their regulation and function. This includes the ability of human (h) but not mouse (m) GH to bind the prolactin (PRL) receptor (PRLR) as well as the GH receptor (GHR). Potential differential effects were assessed in male hGH- or mGH-expressing mice and fed high fat diet (HFD) versus regular chow diet (RCD). Pancreas and epididymal white adipose tissue (eWAT) gene expression and/or related function were targeted as the pancreas responds to both PRLR and GHR signaling and catabolic effects like lipolytic activity are more directly attributable to GH and GHR signaling. Design A transgenic CD-1 mouse expressing hGH but not mGH under hypothalamic control was generated to compare with wild type CD-1 mice and size and bone density determined. Glucose clearance, islet area, insulin and insulin-like growth factor (IGF) -2 gene expression were assessed as well as serum glucose and insulin levels in mice fed a HFD versus RCD for 8 and 24 weeks. Adiposity, liver and serum triglycerides as well as eWAT cell area, cytokine (leptin and adiponectin) and senescence-related marker (p21 CIP1 and p16 INK4a ) RNA levels were also assessed. Results Male hGH-expressing transgenic CD-1[ΔmGH.hGH] mice have significantly lower liver IGF-1 RNA levels and are smaller based on length and weight than wild type CD-1[mGH] mice. They also have ∼1.5-fold higher total body fat and serum triglyceride levels. However, CD-1[ΔmGH.hGH] and CD-1[mGH] mice grow at the same rate with similar cortical and trabecular bone densities. Unlike CD-1[mGH] mice, there was no significant delay in glucose clearance in CD-1[ΔmGH.hGH] mice after 8 weeks on a HFD versus RCD; while basal (RCD) serum insulin levels were similar, fasting glucose levels were lower and pancreas IGF-2 RNA levels were increased in CD-1[ΔmGH.hGH] mice. However, both CD-1[ΔmGH.hGH] and CD-1[mGH] showed evidence of increased insulin resistance after 24 weeks on HFD, including delayed glucose clearance in spite of increased pancreatic islet area and insulin production as well as signs of liver steatosis and increased hepatic triglyceride levels. These increases correlated with elevated PRLR but not GHR RNA levels. Assessment of eWAT revealed >2-fold larger adipocytes in CD-1[ΔmGH.hGH] compared to CD-1 [mGH] mice fed RCD at both 12 and 28 weeks. This was associated with an ∼2.6-fold increase in leptin RNA levels at 12 weeks and ∼58% lower adiponectin RNA levels at 28 weeks. A >2-fold increase in p21 CIP1 transcript levels was also detected in eWAT from both CD-1[ΔmGH.hGH] and CD-1 [mGH] mice fed RCD with age (28 versus 12 weeks) but were unaffected by diet. However, a >2-fold increase in p16 INK4a RNA levels was observed after 24 weeks on HFD. Conclusions While limited to observations in the male, transgenic CD-1[ΔmGH.hGH] mice exhibit signs of GH insufficiency and eWAT adipocyte dysfunction. These mice also show an initial resistance to the negative effects of HFD on glucose clearance when compared to CD-1[mGH] mice, which is potentially related to a differential effect of hGH versus mGH on pancreas development and/or function.

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