Effect of Growth Hormone on Susceptibility to Diet-Induced Obesity

Abstract

Mice with a deficiency in GH function due to disruption of the GH receptor/binding protein gene (GHR(-/-)) are long lived, insulin sensitive, and obese, whereas mice with excess GH function due to expression of a bovine GH transgene (bGH) are short lived, glucose intolerant, and lean. When challenged with a high-fat (HF) diet, we hypothesized that these mice would be differentially susceptible to diet-induced obesity. To test this hypothesis, GHR(-/-), bGH, and littermate control (WT) mice were fed a HF diet (40% kcal) or a nutrient-matched low-fat diet (9% kcal) for 12 wk. On the HF diet, all mice, regardless of genotype, showed a similar percent weight gain and exhibited a significant increase in percent body fat and the mass of epididymal, retroperitoneal, and sc fat pads. For bGH mice, the increase in adipose tissue was relatively small, compared with the WT or GHR(-/-) mice, suggesting some resiliency, although not immunity, to diet-induced obesity. GHR(-/-) mice, which are relatively obese on a low-fat diet, responded to the dietary challenge in a manner similar to WT controls. With HF feeding, all genotypes experienced an increase in insulin levels and depot-dependent effect of adipose tissue. Together, these results further support a role for GH in energy balance regulation and nutrient partitioning. More importantly, because there were genotype-specific effects of diet, these data stress the importance of diet selection and sampling multiple adipose depots in studies with these mouse models.

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

“…Third, GH-induced WAT loss was specific to subcutaneous and mesenteric fat. This result agrees with previously published work in which subcutaneous WAT depots were found to be increased in mice that lacked GH action (10)(11)(12). Thus, these data further support the notion that 'not all WAT depots are treated equally' in terms of GH action and should be evaluated independently in studies with GH or other treatments.…”

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

“…The subcutaneous (inguinal) and visceral (mesenteric) fat pads were the most impacted, while the epididymal fat pad was least altered with growth hormone treatment. Depot-specific effects of growth hormone have been reported previously [21,22]. Thus, these data further support the notion that all fat depots should be evaluated independently in studies with growth hormone or other hormonal treatments.…”

“…In contrast, the gains in lean mass became more prominent with each additional week of treatment. The ability of growth hormone to protect mice from diet-induced fat accumulation and to redirect nutrient partitioning away from adipose tissue and into lean tissue has been reported previously in growth hormone transgenic mice [21,23]. However, both of these studies used mice engineered to have chronically elevated growth hormone levels, representing more of an acromegalic state, and not a daily dosing therapy as performed in this study.…”

Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo

“…Growth hormone receptor (GHR Ϫ/Ϫ ) deficient mice, like Par-1b nulls, exhibit increased insulin sensitivity and growth retardation. However, unlike Par-1b null mice, GHR Ϫ/Ϫ mice also display increased adiposity with age, susceptibility to diet-induced obesity, reduced body temperatures and normal embryonic growth (39)(40)(41). These data suggest that the Par-1b Ϫ/Ϫ metabolic phenotypes described here are not likely to be solely a result of GHmediated effects.…”