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Lipin Expression Is Attenuated in Adipose Tissue of Insulin-Resistant Human Subjects and Increases With Peroxisome Proliferator–Activated Receptor Activation

¹ Department of Medicine, Division of Endocrinology, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas
² Departments of Medicine and Human Genetics, VA Greater Los Angeles Healthcare System, University of California at Los Angeles, Los Angeles, California
³ Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
⁴ Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Address correspondence and reprint requests to Philip A. Kern, MD, Associate Chief of Staff, Research, Central Arkansas Veterans Healthcare System, 598/151 LR, 4300 West 7th St., Little Rock, AR 72205. E-mail: kernphilipa{at}uams.edu

Abbreviations: CPT, carnitine palmitoyltransferase; DMEM, Dulbecco’s modified Eagle’s medium; FSIGT, frequently sampled intravenous glucose tolerance test; IMCL, intramyocellular lipid; PPAR, peroxisome proliferator–activated receptor; TZD, thiazolidinedione

Lipin- and -ß are the alternatively spliced gene products of the Lpin1 gene, whose product lipin is required for adipocyte differentiation. Lipin deficiency causes lipodystrophy, fatty liver, and insulin resistance in mice, whereas adipose tissue lipin overexpression results in increased adiposity but improved insulin sensitivity. To assess lipin expression and its relation to insulin resistance in humans, we examined lipin- and -ß mRNA levels in subjects with normal or impaired glucose tolerance. We found higher expression levels of both lipin isoforms in lean, insulin-sensitive subjects. When compared with normal glucose-tolerant subjects, individuals with impaired glucose tolerance were more insulin resistant, demonstrated higher levels of intramyocellular lipids (IMCLs), and expressed 50% lower levels of lipin- and -ß. In addition, there was a strong inverse correlation between adipose tissue lipin expression and muscle IMCLs but no evidence for an increase in muscle lipid oxidation. After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (S_i) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-ß (but not lipin-) expression by 200% (P < 0.005). Lipin expression in skeletal muscle, however, was not related to obesity or insulin resistance. Hence, high adipose tissue lipin expression is found in insulin-sensitive subjects, and lipin-ß expression increases following treatment with pioglitazone. These results suggest that increased adipogenesis and/or lipogenesis in subcutaneous fat, mediated by the LPIN1 gene, may prevent lipotoxicity in muscle, leading to improved insulin sensitivity.

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