Abstract
As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the α-glucosidase inhibitor (α-GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of α-GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion.
Highlights
Glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide 1 (GLP-1), are the principal incretins that potentiate insulin secretion from pancreatic β cells and reduce postprandial hyperglycemia [1]
We examined the high-fat diet (HFD)-induced increase of GIP mRNA expression in both the duodenum and the terminal ileum (Figure 2A)
Shibue et al found that HFD increased GIP secretion through the binding of meal-derived free fatty acids to fatty acid binding protein 5 (FABP5) [7]
Summary
Glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide 1 (GLP-1), are the principal incretins that potentiate insulin secretion from pancreatic β cells and reduce postprandial hyperglycemia [1]. A connection between obesity and GIP has been reported: Plasma GIP levels in obese humans are increased [4], and GIPR knockout mice are resistant to high-fat diet (HFD)-induced obesity [5]. HFD feeding was found to increase mRNA expression of GIP [6] and to induce obesity through the binding of meal-derived free fatty acids to its binding protein, fatty acid binding protein 5 (FABP5) [7]. They found that induction of HFD-induced obesity requires GIP function using knockout mice of GIP and/or FABP5 [7]. In contrast to the well-defined action of GIP on adipose tissues, the regulatory mechanism of GIP secretion in the context of obesity has not been fully clarified
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