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  • Here we examined whether complete ablation of GIP

    2022-07-07

    Here, we examined whether complete ablation of GIP production could reduce weight gain in the absence of the adipocyte hormone leptin, a condition that results in extreme hyperphagia, obesity, hyperinsulinemia, and insulin resistance, in both mice [24] and humans [25]. We found that Lepob/ob mice became equally obese and insulin resistant whether or not GIP was present, suggesting that GIP antagonism is unlikely to be effective at improving metabolism in extreme obesity associated with defective leptin action.
    Materials and methods
    Results
    Discussion Currently, the only therapy leading to substantial and sustained body weight is bariatric surgery. These procedures can also produce a remarkable resolution of type 2 diabetes within days after surgery, long before any significant weight loss takes place, leading some to perform bariatric surgery to treat diabetes even in non-obese individuals [26], [27], [28]. The altered flow of nutrients in the gut following bariatric surgery may be associated with adaptive changes in the enteroendocrine cell populations [29], [30], [31] and altered production of gastrointestinal hormones, including increases in plasma GIP and GLP-1 levels post surgery [28], [32], [33]. Changes in basal and/or postprandial release of gut hormones are among the potential mechanisms of improved glucose homeostasis and weight loss following bariatric surgery [34], [35]. Therefore, it may be possible to mimic the effects of surgery by gut hormone delivery and single-molecule peptides integrating the complementary actions of multiple hormones have demonstrated promising results [5]. A unimolecular dual incretin derived from intermixed sequences of GLP-1 and GIP demonstrated enhanced anti-hyperglycemic efficacy relative to selective GLP-1 agonists in rodents, monkeys, and humans [36]. Furthermore, while a selective GIP agonist did not alter body weight in high fat fed mice, the co-agonist treatment produced significant weight loss [36]. Even greater efficacy was obtained in high fat fed mice with a tritagonist incorporating a glucagon sequence for the synergistic action of glucagon to increase Zalcitabine expenditure [37]. Therefore, activation of GIP receptors could be part of an effective strategy to treat diabetes and obesity. Shortly after its discovery, endogenous GIP was implicated in linking over-nutrition to the development of obesity [38], [39], in part because the expression of GIP appears to be coordinated with nutritional status. Oral fat is a potent stimulator of GIP release that is augmented by bile, and mediated through direct actions on K-cells via fatty acid-binding protein 5 and G protein-coupled receptor 120 [40], [41]. Diets rich in fat increase intestinal K-cell number [42], GIP expression and circulating GIP levels [43], and the GIP response to oral glucose is enhanced by prior exposure to a high-fat diet [44]. Obese individuals have elevated plasma GIP levels that are associated with reduced post-prandial plasma triglycerides, suggesting a role for GIP in triglyceride uptake [39], [45]. GIP reduces plasma triglyceride increments following meals [46], an effect that could be mediated in part by increasing the activity of lipoprotein lipase, by direct actions of GIP on adipocytes [47], [48]. In some rodent models of obesity, the insulinotropic action of GIP is no longer restrained at basal glucose levels and thus can contribute to hyperinsulinemia [44]. We observed marked elevations of both GIP and insulin in Lepob/ob mice and perhaps their combined anabolic activity contributed to the excessive fat mass. Consistent with a role of GIP in fat accumulation, GIP receptor knockout mice were protected from weight gain and hepatic steatosis when placed on a high fat diet [12], [49]. Moreover, when crossed onto mice with the ob mutation, the severity of obesity in homozygous offspring was reduced by 23%, although these mice remained almost twice the weight of control mice [12]. These findings contrast our observations in which complete ablation of GIP in homozygous ob/ob mice had no impact on weight gain, while hepatic fat content was modestly reduced. It is difficult to reconcile these differences resulting from knockout of GIP versus its receptor, particularly as alternate endogenous ligands for the GIP receptor have not been reported. Perhaps variations in diets, housing conditions or mouse microbiomes contributed to the differences. In our studies, Lepob/ob/GIPgfp/gfp mice had insulin levels equivalent to Lepob/ob/GIP+/+ mice at 8 weeks of age and lower insulin levels at 21 weeks, yet they still remained severely hyperinsulinemic. In contrast, we previously observed a complete normalization of insulin levels in GIP knockout mice on high fat diet, associated with a significant reduction in weight gain relative to wild type controls [21]. A reduction in insulin production has been demonstrated to dramatically reduce weight gain in both ob/ob mice [50] and mice on a high fat diet [51]. We speculate that the reduction in insulin achieved in the Lepob/ob/GIPgfp/gfp animals in our current study was insufficient to promote weight loss.