Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
| Autor: | Jing Gao, Takahito Otani, Masato Hirata, Satoru Mukai, Tomoyo Kawakubo-Yasukochi, Ronghao Tang, Akiko Mizokami, Sakura Chishaki, Hiroshi Takeuchi, Eijiro Jimi, Takashi Kanematsu, Tomomi Sano, Miho Matsuda |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
eWAT epididymal white adipose tissue obesity Adipose tissue Hormone-sensitive lipase HFS high-fat and high-sucrose Biochemistry Receptors G-Protein-Coupled chemistry.chemical_compound Mice Adipocyte Conditional gene knockout Adipocytes Insulin RER respiratory exchange ratio GluOC uncarboxylated form of osteocalcin Mice Knockout NEFA nonesterified fatty acid Adipose Tissue FoxO1 forkhead box O1 GTT glucose tolerance test HSL hormone-sensitive lipase adipose triglyceride lipase (ATGL) Research Article medicine.medical_specialty forkhead box O1 (FoxO1) Lipolysis Osteocalcin GPRC6A adipocyte 03 medical and health sciences Internal medicine 3T3-L1 Cells medicine Animals Humans db-cAMP dibutyryl-cAMP IRF4 interferon regulatory factor 4 Molecular Biology Inflammation PTT pyruvate tolerance test ATGL adipose triglyceride lipase 030102 biochemistry & molecular biology PKI protein kinase A inhibitor Cell Biology Lipase Glucose Tolerance Test 030104 developmental biology Endocrinology chemistry G protein–coupled receptor Adipose triglyceride lipase PKA protein kinase A Adipocyte hypertrophy Insulin Resistance |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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