Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis

Abstract

The G protein–coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in WT mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat and high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity because of downregulation of lipolytic enzymes such as adipose triglyceride lipase and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of adipose triglyceride lipase in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders.

Twelve weeks of a diet and exercise intervention alters the acute bone response to exercise in adolescent females with overweight/obesity

“…This finding was expected, as previous studies in normal-weight adults ( Scott et al, 2010 ) and children ( Pomerants et al, 2008 ; Theocharidis et al, 2020 ) rarely detect increases in bone formation (i.e., P1NP) following acute exercise ( Dolan et al, 2020 ). In addition, this analysis only included a measure of total OC, and not the assessment of other proteoforms of OC (e.g., undercarboxylated) which are known to influence metabolism ( Mizokami et al, 2013 ; Rehder et al, 2015 ; Tsuka et al, 2015 ; Gao et al, 2016 ; Guo et al, 2017 ; Mukai et al, 2021 ). Taken together, our study does not support the effect of a diet and exercise intervention influencing OC’s response to acute exercise in adolescent females with OW/OB.…”

Population genetic structure analysis and identification of backfat thickness loci of Chinese synthetic Yunan pigs

“…Both directions had both Duroc origin (Yunan-Duroc VS. Huainan) and Huainan origin (Yunan-Huainan VS. Duroc). For example, GPRC6A ( Mukai et al, 2021 ) and MBD5 ( Du et al, 2012 ) for fatness and growth of Duroc while ANGPTL3 ( Jiang et al, 2018 ) and DOCK3 ( Reid et al, 2020 ) of Huainan. These results indicated that both Duroc and Huainan pigs had genetic variants affecting growth and fat deposition.…”

ucOCN Inhibits Chondrocyte Hypertrophy and Osteoarthritis Development through GPRC6A/HIF-1α Cascade

“…Next, we investigated how ucOCN regulates chondrocyte hypertrophy. OCN signal in peripheral system is mediated by GPRC6A, such as that in muscle, adipose tissue and some cancer cells [30][31][32] . Therefore, we generated co-immunoprecipitation (Co-IP) of OCN and GPRC6A in chondrocytes, and managed to validate the combination of OCN with GPRC6A (Fig.…”