Human Molecular Genetics Advance Access originally published online on December 15, 2005
Human Molecular Genetics 2006 15(3):377-386; doi:10.1093/hmg/ddi448
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Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism
1Department of Molecular Medicine, National Public Health Institute and 2Department of Medical Genetics, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland, 3Department of Human Genetics and 4Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, USA, 5Biomedicum Bioinformatics Unit, 6Department of Medicine and 7Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland, 8Department of Mental Health and Alcohol Research and 9Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland, 10Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland and 11The Broad Institute, MIT, Boston, MA, USA
* To whom correspondence should be addressed at: Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland. Tel: +358 947448393; Fax: +358 947448480; Email: leena.peltonen{at}ktl.fi
Received August 5, 2005; Accepted December 3, 2005
Recent studies in the mouse have demonstrated that variations in lipin expression levels in adipose tissue have marked effects on adipose tissue mass and insulin sensitivity. In the mouse, lipin deficiency prevents normal adipose tissue development, resulting in lipodystrophy and insulin resistance, whereas excess lipin levels promote fat accumulation and insulin sensitivity. Here, we investigated the effects of genetic variation in lipin levels on glucose homeostasis across species by analyzing lipin transcript levels in human and mouse adipose tissues. A strong negative correlation was observed between lipin mRNA levels and fasting glucose and insulin levels, as well as an indicator of insulin resistance (HOMA-IR), in both mice and humans. We subsequently analyzed the allelic diversity of the LPIN1 gene in dyslipidemic Finnish families, as well as in a case–control sample of obese (n=477) and lean (n=821) individuals. Alleles were defined by genotyping seven single nucleotide polymorphisms (SNPs) of the critical DNA region over the LPIN1 gene. Intragenic SNPs and corresponding allelic haplotypes exhibited associations with serum insulin levels and body mass index (P=0.002–0.04). Both the expression levels in adipose tissue across species and genetic data in human study samples highlight the importance of lipin in glucose homeostasis and imply that allelic variants of this gene have significance in human metabolic traits.
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