Absence of GIP secretion alleviates age-related obesity and insulin resistance

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP−/−) and heterozygous (GIP+/−) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP−/− mice compared to that in WT and GIP+/− mice from 38 weeks of age, while there was no significant difference between WT and GIP+/− mice. Visceral and s.c. fat mass were also significantly lower in GIP−/− mice compared to those in WT and GIP+/− mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP−/− mice than those in WT and GIP+/− mice. During insulin tolerance test, GIP−/− mice showed higher insulin sensitivity than that of WT and GIP+/− mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP−/− mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.

Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota

“…By contrast, the fact that we did not see any difference between Mgll −/− and WT mice in GLP-1 release, the first and most important effect of activation of GPR119 [67], suggests that this latter receptor is instead unlikely to be involved in any of the phenotypic differences observed here between the two genotypes. On the other hand, plasma GIP levels, another response associated with GPR119 activation, were not elevated in Mgll −/− mice following a HFD, as they were in WT mice, in agreement with previous findings of a negative role of this peptide in obesity and/or insulin resistance [68]. In fact, the plasma levels of endocrine mediators were found here to strongly correlate with the relative abundance of some gut bacterial families in a manner (positively or negatively) that was generally in agreement with the reciprocal proposed protective or exacerbating roles of these peptides in obesity and diabetes and with the aforementioned proposed metabolic function of the microbial families therewith correlated.…”

GIPR Function in the Central Nervous System: Implications and Novel Perspectives for GIP-Based Therapies in Treating Metabolic Disorders

“…Despite early studies recognizing the therapeutic potential of GIP to promote storage of dietary triglyceride in WAT [31], data collected from genetic knock-out studies (Gip or Gipr) suggested that in the absence of a functional GIP axis, mice are protected from diet-induced obesity [14,32]. This inspired the hypothesis that GIP is an obesogenic factor, and the suggestion that inhibiting GIP activity is a viable approach for treating obesity and T2D [15].…”

Glucose Tolerance after Pancreatectomy: A Prospective Observational Follow-Up Study of Pancreaticoduodenectomy and Distal Pancreatectomy

“…Another study demonstrated improved insulin resistance in GIP-knockout mice. 35 It is possible that the altered gastrointestinal tract improves insulin resistance via changes in the release of gastrointestinal hormones such as GLP-1 and GIP. In summary, improved insulin resistance after PD might be explained by changes in the gastrointestinal tract and hormonal secretion.…”