Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms

Abstract

Background Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox. Scope of the review This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R. Major conclusions There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.

GIPR Signaling in Immune Cells Maintains Metabolically Beneficial Type 2 Immune Responses in the White Fat From Obese Mice

“…While loss-of-function studies indicate that GIP drives weight gain, when it comes to GIPR agonism and antagonism, compelling evidence paradoxically indicate that both approaches can reduce body weight, especially if combined with GLP-1 agonists (12,59). This paradox may reflect the partial agonistic activity of certain antagonists (60), compensatory relationship and overlapping signaling axes between GIPR and GLP-1R incretin receptors (59,61), as well as desensitization of GIPR achieved by chronic agonism (62). With respect to the latter, in cultured mouse or human preadipocytes, exposure to 1 mM dAla2-GIP for 24 h decreased cAMP response to subsequent GIPR stimulation up to 48 h (62), indicating that chronic GIPR agonism functionally mimics GIPR antagonism.…”

The evolving story of incretins (GIP and GLP‐1) in metabolic and cardiovascular disease: A pathophysiological update

“…Thus, opposing therapeutic measures are claimed to be beneficial for obesity, metabolic syndrome and type 2 diabetes. A recent review by Campbell has summarized these findings and suggests some mechanisms explaining these apparently contradictory approaches, 131 which both have been extensively studied (Table S1). Predominant patterns for therapeutic effects of GIP agonism as well as antagonism in preventing diet‐induced obesity and in reducing body weight in pre‐existing obesity detected in Table S1 have been summarized as Table 3.…”

“…Both GIP receptor agonism and antagonisms have been described to reduce body weight or prevent diet‐induced obesity 131 …”

The Role of GIP Receptor in the CNS for the Pathogenesis of Obesity

“…In light of the energy balance equation, energy expenditure must exceed energy intake for weight loss to occur. This remains true for GIP-mediated weight loss, which induces increased energy expenditure, decreased food intake, or both (35). As the brain affects both energy intake and expenditure, it is possible that the central nervous system (CNS) mediates GIP action.…”