GIP receptor deletion in mice confers resistance to high-fat diet-induced obesity via alterations in energy expenditure and adipose tissue lipid metabolism

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is best known as an incretin hormone that is secreted from K-cells of the proximal intestine, but evidence also implicates a role for GIP in regulating lipid metabolism and adiposity. It is well established that GIP receptor knockout (GIPR KO) mice are resistant to diet-induced obesity; however, the factors mediating this effect remain unresolved. Accordingly, we aimed to elucidate the mechanisms leading to adiposity resistance in GIPR KO mice with a focus on whole-body energy balance and lipid metabolism in adipose tissues. Studies were conducted in age-matched male GIPR KO and wild type (WT) mice fed a high-fat diet for 10 weeks. GIPR KO mice gained less body weight and fat mass compared to WT littermates, and this was associated with increased energy expenditure but no differences in food intake or faecal energy loss. Upon an oral lipid challenge, fatty acid storage in inguinal adipose tissue was significantly increased in GIPR KO compared with WT mice. This was not related to differential expression of lipoprotein lipase in adipose tissue. Adipose tissue lipolysis was increased in GIPR KO compared with WT mice, particularly following b-adrenergic stimulation, and could explain why GIPR KO mice gain less adipose tissue despite increased rates of fatty acid storage in inguinal adipose tissue. Taken together, these results suggest that the GIPR is required for normal maintenance of body weight and adipose tissue mass by regulating energy expenditure and lipolysis.

Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes

“…These results suggest that GIPR signaling contributes to regulation of body weight and body composition, and that reduced GIPR signaling is a potentially beneficial strategy against obesity. In support, obese Gipr knockout mice show lower body weight gain compared to wild-type mice, which may be explained by a lower fat mass, lean tissue mass and food intake, and an increased physical activity in these mice ( Boer et al, 2021 ; Zhang et al, 2021 ). In the present study, we did not see an increased self-reported physical activity among carriers of R190Q or E288G.…”

Glucose‐dependent insulinotropic polypeptide receptor antagonist treatment causes a reduction in weight gain in ovariectomised high fat diet‐fed mice

“…Antagonism of the GIP receptor has received much attention as a potential target for obesity therapy, strongly supported by studies showing that deletion of the GIP receptor in mice resulted in resistance to diet‐induced weight gain (Boer, Keenan, et al, 2021; Hansotia et al, 2007; Miyawaki et al, 2002; Naitoh et al, 2008). In this study, we characterized the in vitro and in vivo pharmacological properties of a novel GIPR antagonist, mGIPAnt‐1.…”

“…Treatment of diet‐induced obese mice with an antagonistic GIP receptor antibody reduced food consumption (Killion et al, 2018), whereas the small‐molecule compound SKL‐14959 suppressed weight gain without affecting food consumption (Nakamura et al, 2018). Whereas studies utilizing mouse models of GIP receptor KO have consistently shown that GIP receptor KO results in resistance to the development of obesity, conflicting data have been reported on food intake, with one study showing decreased food intake in the GIP receptor KO mice (Hansotia et al, 2007) and others showing no difference between GIP receptor KO and WT groups (Boer, Keenan, et al, 2021; Miyawaki et al, 2002; Naitoh et al, 2008). Double incretin receptor knockout mice likewise are resistant to diet‐induced obesity, although this is paired with an increase in food intake compared to WT littermates, when corrected for body weight (Hansotia et al, 2007).…”

“…Further studies are required to assess how treatment with mGIPAnt‐1 could affect food intake in mice. In a recent study, we showed that the resistance to diet‐induced weight gain commonly shown in GIP receptor KO mice can be at least in part be explained by enhanced energy expenditure and activity levels, as well as increased lipolysis in iWAT and eWAT (Boer, Keenan, et al, 2021). Interestingly, we found that GIP receptor KO had increased postprandial lipid storage in iWAT.…”

“…In vivo biological activity of mGIPAnt‐1 was determined with an intraperitoneal glucose tolerance test with n = 8–12 and the HFD study was performed with n = 11–12, ), where n = number of independent values. Sample sizes for experiments were determined based on previous studies (Boer, Hartmann, & Holst, 2021; Boer, Keenan, et al, 2021). To ensure blinding regarding treatment, compounds were coded by an independent party.…”