INCRETIN EFFECTS ON GENE EXPRESSION DURING ADIPOGENESIS [P3-350]
Hadden TJ, Miller RE; Res Service, John D Dingell VA Medical Center, Detroit, MI;
Internal Medicine, Wayne State University, Detroit, MI
Recent research has begun to examine the mechanisms by which the incretins regulate
glucose metabolism and the development of adipose tissue. These studies have shown
that glucagon-like peptide-1 (GLP-1) upregulates glucose receptors, stimulates insulin-mediated
glucose uptake by adipocytes, and improves peripheral insulin resistance.1
Glucose-dependent insulinotropic polypeptide (GIP) is also important in the conversion
of dietary fat to adipose tissue and the differentiation of adipocytes.2 For example, in
vitro studies have examined the effects of incretin exposure on cellular fat metabolism
and adipogenesis using 3T3-L1 cells, a murine-derived cell line that differentiates into
adipocyte-like cells under the proper conditions. The culturing of 3T3-L1 cells with GLP-1 or GIP has been shown to promote cellular lipid accumulation and to stimulate
production of CCAAT/enhancer-binding protein α (C/EBP α), a transcription factor that,
acting in concert with peroxisome proliferator-activated receptor (PPAR)-γ, promotes the
maturation of adipocytes from multipotent mesenchymal stem cells.3
This presentation described new observations on the effects of incretin exposure on gene
expression during adipocyte development. The investigators measured mRNA for the
protein adiponectin in cells that were incubated with GLP-1 or GIP. Adiponectin, a
hormone that is secreted exclusively by adipocytes, regulates several factors that
contribute to the formation of adipose tissue, including tissue responses to lipids, glucose,
and insulin.4 Adiponectin concentration in serum has also recently been examined as a
potential independent marker of increased diabetes risk.5 In addition, the investigators
examined the expression of preadipocyte factor-1 (PREF-1), a protein that is produced by
preadipocytes but not mature adipocytes, and that is used as a specific preadipocyte
marker.6 The investigators found that exposure of 3T3-L1 cells to both GLP-1 and GIP increased adiponectin mRNA, but did not alter mRNA expression of the inflammatory
cytokine tumor necrosis factor-α. When the adipocytes were incubated with GLP-1 or
GIP during the induction of differentiation, the researchers found lower levels of mRNA
for PREF-1, suggesting greater maturation of adipocytes. This effect was not observed
when the cells were incubated with incretins after differentiation.
The investigators concluded that the increased adiponectin and decreased PREF-1 levels
observed in this study suggest that incretins promote the conversion of 3T3-L1 cells to
mature adipocytes. Previous research from this research group has suggested that incretin
exposure results in higher levels of the adipocyte maturation promoting factors PPAR-γ
and C/EBP-α expression, suggesting that activation of these proteins may contribute to
the effect of incretins on adipogenesis.
References
1. Gao H, Wang X, Zhang Z, et al. GLP-1 amplifies insulin signaling by up-regulation of
IRbeta, IRS-1 and Glut4 in 3T3-L1 adipocytes. Endocrine. 2007;32:90-95.
2. Flatt PR. Dorothy Hodgkin Lecture 2008. Gastric inhibitory polypeptide (GIP)
revisited: a new therapeutic target for obesity-diabetes? Diabet Med. 2008;25:759-764.
3. Rosen ED. The transcriptional basis of adipocyte development. Prostaglandins Leukot
Essent Fatty Acids. 2005;73:31-34.
4. Ahima RS. Metabolic actions of adipocyte hormones: focus on adiponectin. Obesity.
2006;14(suppl 1):9S-15S.
5. Sull JW, Kim HJ, Yun JE, et al. Serum adiponectin is associated with family history of
diabetes independently of obesity and insulin resistance in healthy Korean men and
women. Eur J Endocrinol. 2009;160:39-43.
6. Sul HS. Pref-1: role in adipogenesis and mesenchymal cell fate. Mol Endocrinol. 2009
Jun 18. [Epub ahead of print.]
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