title: Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis.
abstract: As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic therapies. There is increasing evidence that mitochondrial malfunction is a pivotal event in disturbing adipocyte cell homeostasis. Among major mitochondrial structure components, the high-affinity drug- and cholesterol-binding outer mitochondrial membrane translocator protein (18 kDa; TSPO) has shown importance across a broad spectrum of mitochondrial functions. Recent studies demonstrated the presence of TSPO in white adipocyte mitochondria of mice, and administration of TSPO drug ligands to obese mice reduced weight gain and lowered glucose level. Therefore, it is of great interest to assess whether TSPO in adipocytes could serve as a drug target to regulate adipocyte activities with potential influence on weight control and glucose metabolism. Two structurally distinct TSPO drug ligands, PK 11195 and FGIN-1-27, improved the intracellular dynamics of 3T3-L1 adipocytes, such as the production and release of adipokines, glucose uptake, and adipogenesis. TSPO knockdown in either differentiated adipocytes or preadipocytes impaired these functions. Findings from 3T3-L1 cells were related to human primary cells, where TSPO expression was tightly associated with the metabolic state of primary adipocytes and the differentiation of primary preadipocytes. These results suggest that TSPO expression is essential to safeguard healthy adipocyte functions, and that TSPO activation in adipocytes improves their metabolic status in regulating glucose homeostasis. Adipocyte TSPO may serve as a pharmacologic target for the treatment of obesity and diabetes.
authors.affiliation: Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Jiehan
authors.initials: J
authors.lastname: Li
authors.affiliation: Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada; Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada; Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada. Electronic address: vassilios.papadopoulos@mcgill.ca.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D041721:3T3-L1 Cells; D052437:Adipocytes, Brown / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D054392:Adipokines / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D034622:RNA Interference; D018079:Receptors, GABA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D054392:Adipokines; D019440:Anti-Obesity Agents; C463819:Bzrp protein, mouse; D007004:Hypoglycemic Agents; D007210:Indoleacetic Acids; D007546:Isoquinolines; D008024:Ligands; D018079:Receptors, GABA; C499229:TSPO protein, human; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D005947:Glucose; C037850:PK 11195
keywords: Adipocyte mitochondria; Browning; Glucose homeostasis; Obesity and diabetes; PK 11195; TSPO