Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis

Abstract

Summary Growth hormone (GH) binds to its receptor (growth hormone receptor [GHR]) to exert its pleiotropic effects on growth and metabolism. Disrupted GH/GHR actions not only fail growth but also are involved in many metabolic disorders, as shown in murine models with global or tissue-specific Ghr deficiency and clinical observations. Here we constructed an adipose-specific Ghr knockout mouse model Ad-GHRKO and studied the metabolic adaptability of the mice when stressed by high-fat diet (HFD) or cold. We found that disruption of adipose Ghr accelerated dietary obesity but protected the liver from ectopic adiposity through free fatty acid trapping. The heat-producing brown adipose tissue burning and white adipose tissue browning induced by cold were slowed in the absence of adipose Ghr but were recovered after prolonged cold acclimation. We conclude that at the expense of excessive subcutaneous fat accumulation and lower emergent cold tolerance, down-tuning adipose GHR signaling emulates a healthy obesity situation which has metabolic advantages against HFD.

Vitamin D deficiency serves as a precursor to stunted growth and central adiposity in zebrafish

“…Given our combined stunted growth and obese phenotypes, we sought to determine if GH signaling was modulated in our model. Previous studies using adipose tissue-specific GHR knockout (Ad-GHRKO) mice demonstrate similar disruptions in metabolic homeostasis 37 . Ad-GHRKO knockout mice exhibit no disruption in global GH or IGF signaling, or changes in serum glucose levels, and axial growth 37 .…”

“…Previous studies using adipose tissue-specific GHR knockout (Ad-GHRKO) mice demonstrate similar disruptions in metabolic homeostasis 37 . Ad-GHRKO knockout mice exhibit no disruption in global GH or IGF signaling, or changes in serum glucose levels, and axial growth 37 . Rather, these KO mice demonstrate significant increases in body weight, hypertrophy and hyperplasia of AT, decreased lipolysis, and resistance to hepatic steatosis, phenotypes much in line with our VDD zebrafish 37 .…”

“…Ad-GHRKO knockout mice exhibit no disruption in global GH or IGF signaling, or changes in serum glucose levels, and axial growth 37 . Rather, these KO mice demonstrate significant increases in body weight, hypertrophy and hyperplasia of AT, decreased lipolysis, and resistance to hepatic steatosis, phenotypes much in line with our VDD zebrafish 37 . Similarly, vizzini zebrafish mutants, which contain a premature stop codon in gh1 , demonstrate no disruption in global IGF signaling, but exhibit stunted growth, hyperplasia and hypertrophy of AT, and decreased mobilization of AT during periods of starvation 28 .…”

The effectiveness of growth hormone replacement on energy expenditure and body composition in patients with adult growth hormone deficiency

“…In addition, it was confirmed that the basal metabolic rate per kilogram of LBM increased after GH treatment. It has been demonstrated that the brown adipose tissue is characterized by a high mitochondrial content to maintain the body temperature and is involved in energy expenditure, and GH increases the energy expenditure by binding to the adipose GH receptors [17]. This pathway is considered as one of the mechanisms that increases the REE by GH replacement therapy in patients with AGHD.…”

Tissue-Specific GHR Knockout Mice: An Updated Review

“…In a second study, Ran et al ( 10 ) subjected the AdGHRKO to a high fat (HF) diet (HFD) and cold stress to study the metabolic adaptability of the mice. It was found that disruption of adipose GH signaling attenuated hyperglycemia and the insulin resistance accompanying diet-induced obesity by improving glucose homeostasis.…”