Insulin, IGF-1, and GH Receptors Are Altered in an Adipose Tissue Depot–Specific Manner in Male Mice With Modified GH Action

Abstract

Growth hormone (GH) is a determinant of glucose homeostasis and adipose tissue (AT) function. Using 7-month-old transgenic mice expressing the bovine growth hormone (bGH) gene and growth hormone receptor knockout (GHR-/-) mice, we examined whether changes in GH action affect glucose, insulin, and pyruvate tolerance and AT expression of proteins involved in the interrelated signaling pathways of GH, insulinlike growth factor 1 (IGF-1), and insulin. Furthermore, we searched for AT depot-specific differences in control mice. Glycated hemoglobin levels were reduced in bGH and GHR-/- mice, and bGH mice displayed impaired gluconeogenesis as judged by pyruvate tolerance testing. Serum IGF-1 was elevated by 90% in bGH mice, whereas IGF-1 and insulin were reduced by 97% and 61% in GHR-/- mice, respectively. Igf1 RNA was increased in subcutaneous, epididymal, retroperitoneal, and brown adipose tissue (BAT) depots in bGH mice (mean increase ± standard error of the mean in all five depots, 153% ± 27%) and decreased in all depots in GHR-/- mice (mean decrease, 62% ± 4%). IGF-1 receptor expression was decreased in all AT depots of bGH mice (mean decrease, 49% ± 6%) and increased in all AT depots of GHR-/- mice (mean increase, 94% ± 8%). Insulin receptor expression was reduced in retroperitoneal, mesenteric, and BAT depots in bGH mice (mean decrease in all depots, 56% ± 4%) and augmented in subcutaneous, retroperitoneal, mesenteric, and BAT depots in GHR-/- mice (mean increase: 51% ± 1%). Collectively, our findings indicate a role for GH in influencing hormone signaling in AT in a depot-dependent manner.

The effects of growth hormone on adipose tissue: old observations, new mechanisms

“…Furthermore, the capacity of preadipocytes for proliferation and differentiation is dependent on the depot of origin of the isolated cells 130 . Of note, adipose tissue depot differences in insulin receptor, IGF1 receptor and GHR have also been reported, with highest IGF1 receptor (IGF1R) expression in epididymal and mesenteric depots, higher insulin receptor expression in retroperitoneal and mesenteric depots and highest GHR expression in the retroperitoneal depot 131 . This finding is important for the hormone responsiveness of specific depots.…”

GHR−/− Mice are protected from obesity‐related white adipose tissue inflammation

“…Depot differences in GHR −/− mice are not limited to size of the depot. In a previous study investigating the expression of GH‐related genes in GHR –/– mice in different adipose depots, 33 GHR −/− SubQ was found to have increased insulin receptor and inslulin‐like growth factor (IGF)‐1 receptor gene expression and decreased IGF‐1 expression. GHR −/− Epi, on the other hand, have increased IGF‐1 receptor gene expression, decreased IGF‐1 gene expression and no change in insulin receptor expression, whereas GHR −/− Mes have increased insulin receptor and IGF‐1 receptor gene expression and no change in IGF‐1 expression.…”

“…Depot differences in GHR −/− mice are not limited to size of the depot. In a previous study investigating the expression of GH-related genes in GHR -/mice in different adipose depots, 33 has been reported with decreased fertility when Epi is depleted 48 or regarding the divergent adipogenesis profiles of each depot. 49 In addition, functional studies will be important to determine the metabolic phenotype, the pathogen sensing machinery, and the immune cell trafficking mechanisms in the absence of GH in WAT immune cells.…”

Mice with gene alterations in the GH and IGF family

“…Interestingly, both male and female mice also have increased adiposity in early life but switch to a leaner than normal phenotype at four (males) to six (females) months of age [146]. While GH is known to increase gluconeogenesis, MT1-bGH mice surprisingly exhibit suppressed glucose production following a pyruvate challenge, which could be confounded by higher insulin levels [151]. On HFDs, they are resistant to diet-induced obesity but develop dyslipidemia and diabetes [152].…”