Glucose-dependent insulinotropic polypeptide (GIP) has been shown to have direct effects on non-islet tissues, influencing glucose uptake and lipolysis in adipocytes. New research elucidates the relationship between GIP, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and fatty acid metabolism, demonstrating that GIP reduces free fatty acid (FFA) release from adipose tissue by inhibiting lipolysis, a process dependent on the modulation of 11β-HSD1 activity. This study provides insights into the insulin-independent effects of GIP on adipose tissue, potentially contributing to the understanding of postprandial metabolic regulation.
GIP's Impact on 11β-HSD1 and Lipolysis
In vitro studies using differentiated 3T3-L1 adipocytes revealed that GIP reduces the activity of 11β-HSD1 promoter constructs and the expression and activity of 11β-HSD1 in a time- and dose-dependent manner. This reduction was paralleled by a decrease in FFA release and the expression of key enzymes regulating lipolysis in adipose tissue. Notably, pre-inhibition of 11β-HSD1 completely abolished the GIP-induced effects on FFA release, underscoring the critical role of 11β-HSD1 in mediating GIP's effects.
Clinical Evidence of GIP's Effects in Humans
A randomized clinical trial involving eleven apparently healthy, obese male subjects (BMI 33.5 ± 2.0 kg/m²) was conducted to investigate the acute effects of GIP in humans. The study found that GIP infusion significantly lowered circulating FFAs compared to saline control. Furthermore, GIP reduced the expression and ex vivo activity of 11β-HSD1 and adipose triglyceride lipase (ATGL) expression in subcutaneous fat biopsies. Specifically, GIP treatment decreased 11β-HSD1 mRNA in subcutaneous adipose tissue biopsies by approximately 20% compared to baseline (P < 0.05). Ex vivo 11β-HSD1 enzyme activity also decreased in human adipose tissue by approximately 25% compared to baseline (P < 0.05).
Mechanistic Insights
Further mechanistic investigations revealed that GIP reduces 11β-HSD1 promoter activity in differentiated 3T3-L1 cells, suggesting that at least one element responsive to GIP-dependent signaling is located within the proximal promoter region. Mutation of putative cAMP-responsive element–binding protein 2 (CREB2) and CCAAT/enhancer binding protein (C/EBP) binding sites abolished GIP-induced effects on promoter activity, indicating the involvement of these transcription factors in GIP-induced suppression of 11β-HSD1 expression.
Implications for Metabolic Regulation
The findings suggest that GIP inhibits basal FFA release in adipocytes through direct peripheral effects, partially dependent on the inhibition of the intracellular cortisone-cortisol shuttle 11β-HSD1. These results align with previous studies demonstrating the upregulation of GIP receptors during adipocyte differentiation and improved glucose uptake in GIP-treated adipocytes. The study highlights the potential of GIP in modulating fatty acid metabolism and provides a novel link between incretin-based regulation of peripheral tissue metabolism and 11β-HSD1 under basal conditions.
Study Limitations
The authors acknowledge several limitations, including the lack of analysis of the physiological relevance of the data in the postprandial situation and the exclusive investigation of obese males. The study also points out that the biopsies were not further separated into adipocytes and a stromal vascular fraction. Further research, including rodent experiments with fat-specific 11β-HSD1 knockout mice, is warranted to improve the understanding of GIP-dependent peripheral effects.
