Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. In addition, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.
Glucose-dependent insulinotropic polypeptide (GIP) is a 42–amino acid polypeptide that is produced by enteroendocrine K cells in the proximal small intestine (1,2). In response to nutrient ingestion, GIP is secreted into the circulation, acts directly on the GIP receptor (GIPR) expressed by pancreatic β-cells, and stimulates insulin secretion. Thus, a major role of GIP is to mediate the postprandial potentiation of insulin secretion. Indeed, GIP and glucagon-like peptide 1 (GLP-1), which is another incretin hormone, account for up to 70% of the postprandial insulin response (1,2).
GIP has long been considered an “obese hormone” (3–5). Early studies showed that obese subjects exhibit an exaggerated GIP secretion response following nutrient ingestion as well as elevated fasting GIP levels (6). In animal models of high-fat diet (HFD)-induced obesity, K cell hyperplasia and increased production of GIP were observed (7,8). Furthermore, GIP promotes fat deposition in the adipose tissues (4). Although favorable data to support this model accumulated for many years, direct evidence supporting a role for GIP as an obesogenic signal initially came from a seminal study by Seino and colleagues (5). They showed that mice with GIPR deficiency displayed relatively normal adiposity and body weight when fed a normocaloric diet; however, when challenged with an HFD, these mice gained less body weight and fat mass and reserved normal insulin sensitivity (5). These observations suggest that GIPR deficiency protects mice from diet-induced obesity and insulin resistance, which has subsequently been supported by many studies. Now, inhibition of endogenous GIP or its receptor is generally accepted to confer resistance to HFD-induced obesity. Many methods of inhibition have been tested, including GIP deficiency (9), ablation of GIP-producing K cells (10), neutralizing antibodies against GIP/GIPR (11–14), GIP vaccination (15–17), and pharmacological inhibition of GIPR (18). In addition, recent genome-wide association studies (GWAS) have identified GIPR variants associated with obesity and BMI, some of which are associated with a lower BMI (19–24). Thus, the currently available data strongly suggest that the endogenous GIP-GIPR system plays a role in the pathogenesis of obesity.
In contrast to its assumed obesogenic role, GIP does not promote food intake or adiposity (25–27). Instead, negative energy balance is induced by administration of long-lasting GIP derivatives (28,29) or transgenic overexpression of GIP (30). In addition, GLP-1/GIP hybrid peptides have been shown to induce marked weight loss in preclinical and clinical settings (31,32). The therapeutic efficacy of this combination is superior to that of GLP-1 receptor agonists alone, suggesting that GIP agonism has weight-reducing effects in a pharmacological context. The effect of GIP alone or in combination with GLP-1 on food intake requires central GIPR signaling (29). As such, weight loss can be achieved by either GIPR antagonism or agonism. Whereas the exact underlying mechanism remains unknown, a possible explanation for the paradoxical observations is that chronic GIPR agonism desensitizes GIPR, which ultimately results in creating antag-onism (24). Although GIPR desensitization in adipocytes has been reported (24), recent studies have shown that this phenomenon does not seem to be applicable to the GIPR in β-cells (33,34). Thus, whether GIPR desensitization occurs in the central nervous system (CNS) and mediates the antiobesity effect of GIPR antagonism remains an open question. Nevertheless, manipulation of the GIP system has a profound impact on energy balance.
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 CNS mediates GIP action. However, early studies suggested that intracerebroventricular (ICV) administration of native GIP does not affect food intake (e.g., [25]) and concluded that GIP does not influence feeding behavior. Although GIPR has been identified in the CNS, very few studies have investigated the CNS role of GIPR in energy homeostasis. Recent findings have renewed interest into whether and how GIPR expressed in the brain mediates its physiological and pharmacological effects on energy balance.
In this Perspective, the role of the CNS in energy balance will be outlined, and discoveries delineating the role of GIP in the CNS will be reviewed. Finally, the potential pathophysiological CNS role of GIPR in obesity will be highlighted.
Body weight is tightly regulated by the balance of energy intake and energy output via the neural circuits in the CNS. Neural control of energy balance is achieved through the coordinated integration of multiple neural signals from distinct neural circuits involving the hypothalamus, the hindbrain, the amygdala, prefrontal cortex, hippocampus, and other areas in a complex and redundant manner. The hypothalamus plays a primary role in regulating energy balance, being closely interconnected and reciprocally influencing other neural circuits in the different CNS sites. The hypothalamus is a small region located at the base of the brain and is a highly heterogeneous structure composed of many small nuclei with various functions. Hypothalamic neurons communicate with peripheral organs via circulating factors, such as insulin, leptin, gut hormones, and a variety of nutrients. A key site in the hypothalamus receiving peripheral signals is the arcuate nucleus (ARC) (36). ARC neurons can access the adjacent median eminence, which lacks a functional blood-brain barrier (BBB), permitting ARC neurons to sense blood-borne factors from the periphery (37). This anatomical characteristic makes the ARC an ideal site to respond to peripheral factors and signal to the brain. Within the ARC are two distinct prototypical neuronal populations that yield opposing effects on energy balance: the orexigenic neurons expressing neuropeptide Y and Agouti-related peptide (AgRP/NPY neurons) that promote feeding behavior when activated and the anorexigenic neurons expressing proopiomelanocortin (POMC neurons) that suppress food intake when stimulated (38,39). The ability of orexigenic and anorexigenic neurons to directly respond to circulating hormones and mediate metabolic effects demonstrates that the ARC is a critical site for peripheral metabolic signals.
The central role of the brain in the development and maintenance of obesity has been unequivocally established over the last decades. First, the generation of experimental lesions in the hypothalamus using a stereotaxic apparatus demonstrated that hypothalamic damage causes obesity, firmly establishing the concept of hypothalamic obesity (40). Second, genetic studies of monogenic obesity syndromes support the role of the hypothalamus in human obesity. Many of the genes responsible for human monogenic obesity act through the hypothalamic leptin/melanocortin pathway (41), pointing to the critical role of the hypothalamus in human obesity. Finally, unbiased genetic discovery through GWAS further supports a primary role for the brain in human obesity. GWAS have identified >500 loci associated with BMI and obesity, and the vast majority of the genes located near and/or within the GWAS loci are enriched in the brain or linked to its function (42). Therefore, the CNS is now well established as a critical driver of obesity. Accordingly, studies of central aspects of GIP biology are of increasing importance to fully understand the role of GIP in obesity and its paradoxical antiobesity effects.
GIPR expression has been observed throughout the brain, including CNS sites responsible for energy metabolism. An early autoradiographic analysis of [125 I]GIP identified putative GIPR binding sites in several brain regions (43) but failed to detect GIP binding in the hypothalamus. Other methodologies, such as in situ hybridization, Northern blot, and quantitative PCR (qPCR), also showed broad CNS distribution of GIPR mRNA and included the hypothalamus (13,44–47). Elegant work by Adriaenssens et al. (48) recently revealed the anatomical distribution of GIPR in the CNS at a cellular resolution. They generated a Cre-dependent reporter mouse that enabled the identification of Gipr-positive cells and observed Gipr expression throughout the CNS, including the hypothalamic nuclei (the ARC and dorsomedial and paraventricular nuclei of the hypothalamus) and hindbrain areas that are involved in energy balance. Because this model is a germ line reporter, transient expression of Cre recombinase during development may be possible. Nevertheless, these data suggest that GIPR is present in the CNS regions that are responsible for energy homeostasis and support a CNS role for GIPR in the control of energy balance.
The effect of centrally administered GIP on food intake was studied as early as the 1980s (Table 1). Woods et al. (25) found that a single ICV dose of native GIP at 20 pmol had no effect on food intake in rats. For the next 30 years, the CNS role of GIP in energy balance did not appear in the literature. In 2011, one report demonstrated that chronic ICV administration of native GIP at a supraphysiological dose (2,000 pmol/day) caused significant weight loss in rats, whereas ICV dosing at 20 and 200 pmol/day did not affect body weight or food intake (26). Further, a central bolus injection of GIP suppressed food intake in lean C57BI/6 mice at a higher dose (6,000 pmol) but not at lower doses (1,000 and 3,000 pmol) (27). Similarly, we did not observe changes in food intake or body weight when native GIP was ICV infused at 30 and 3,000 pmol in lean C57BI/6 mice (13,49). Recently, Zhang et al. (29) demonstrated that a long-lasting, fatty acylated GIP agonist suppressed food intake and reduced body weight of diet-induced obese mice when acutely ICV administered at 1,000, 3,000, and 6,000 pmol or when chronically dosed at 20 and 40 pmol/day. Importantly, the weight loss effect of ICV-administered acyl-GIP was blunted in brain-specific GIPR knockout mice (29), suggesting that this effect occurs via GIPR in the CNS. Interestingly, acyl-GIP stimulates c-fos induction (a marker for neural activation) in the ARC (29) where GIPR is expressed (48). Chemogenetic activation of GIPR-expressing cells with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology also resulted in suppressed food intake (48). Thus, food intake and body weight can be clearly reduced by supraphysiological doses of native GIP or administration of a long-lasting GIP derivative.
