OCT1 Expression in adipocytes could contribute to increased metformin action in obese subjects.
OBJECTIVE
Metformin has been well characterized in vitro as a substrate of liver-expressed organic cation transporters (OCTs). We investigated the gene expression and protein levels of OCT-1 and OCT-2 in adipose tissue and during adipogenesis and evaluated their possible role in metformin action on adipocytes.


METHODS
OCT1 and OCT2 gene expressions were analyzed in 118 adipose tissue samples (57 visceral and 61 subcutaneous depots) and during human preadipocyte differentiation. To test the possible role of OCT1 mediating the response of adipocytes to metformin, cotreatments with cimetidine (OCT blocker, 0.5 and 5 mmol/l) and metformin were made on human preadipocytes and subcutaneous adipose tissue (SAT).


RESULTS
OCT1 gene was expressed in both subcutaneous and visceral adipose tissue. In both fat depots, OCT1 gene expression and protein levels were significantly increased in obese subjects. OCT1 gene expression in isolated preadipocytes significantly increased during differentiation in parallel to adipogenic genes. Metformin (5 mmol/l) decreased the expression of lipogenic genes and lipid droplets accumulation while increasing AMP-activated protein kinase (AMPK) activation, preventing differentiation of human preadipocytes. Cotreatment with cimetidine restored adipogenesis. Furthermore, metformin decreased IL-6 and MCP-1 gene expression in comparison with differentiated adipocytes. Metformin (0.1 and 1 mmol/l) decreased adipogenic and inflammatory genes in SAT. OCT2 gene expression was not detected in adipose tissue and was very small in isolated preadipocytes, disappearing during adipogenesis.


CONCLUSIONS
OCT1 gene expression and protein levels are detectable in adipose tissue. Increased OCT1 gene expression in adipose tissue of obese subjects might contribute to increased metformin action in these subjects.
Moreno-Navarrete
José María
JM
Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomédica de Girona, CIBER Fisiopatología de la Obesidad y Nutrición, Spain.
Ortega
Francisco J
FJ
Rodríguez-Hermosa
José-Ignacio
JI
Sabater
Mònica
M
Pardo
Gerard
G
Ricart
Wifredo
W
Fernández-Real
José Manuel
JM
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000123:Acetyltransferases / Q000235:genetics; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000473:pathology / Q000502:physiology*; D001391:Azo Compounds; D002454:Cell Differentiation; D004396:Coloring Agents; D054890:Fatty Acid Synthase, Type I / Q000235:genetics; D015390:Gastric Bypass; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D009765:Obesity / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D027701:Organic Cation Transport Proteins / Q000235:genetics; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D047495:PPAR gamma / Q000235:genetics; D012313:RNA / Q000235:genetics
D001391:Azo Compounds; D004396:Coloring Agents; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D047495:PPAR gamma; C491013:SLC22A2 protein, human; D012313:RNA; D008687:Metformin; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; C011049:oil red O