Introduction
In the landscape of metabolic regulation, two gut-derived hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), emerge as pivotal players. Their integral roles in glucose metabolism and appetite suppression have paved the way for innovative weight loss solutions, particularly through GLP-1 agonists and the more recent development of GLP-1/GIP co-agonists. This article delves into the mechanisms, clinical evidence, and therapeutic potential of targeting GLP-1 and GIP for weight management, contrasting these approaches with traditional weight loss methodologies.
The Roles of GLP-1 and GIP in Metabolic Regulation
GLP-1 and GIP are incretin hormones, meaning they are released from the gut in response to nutrient intake and amplify insulin secretion from pancreatic β-cells. However, their actions extend beyond insulin regulation, influencing various aspects of energy homeostasis.
GLP-1: Appetite Suppression and Gastric Emptying
GLP-1, synthesized by L cells in the intestine, binds to its receptor expressed in various tissues, including β-cells, α cells, kidneys, lungs, gastric mucosa, heart, brain, and immune cells. GLP-1 receptor agonists (GLP-1 RAs) stimulate significant weight loss by reducing gastric emptying, stimulating satiety, and decreasing food intake by acting on peripheral and central receptors in the gut and brain. Liraglutide, for example, crosses the blood-brain barrier, reaching the arcuate nucleus (ARC) where it stimulates neurons that regulate appetite and express pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcripts (CART); liraglutide indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. GLP-1 RAs also reduce blood pressure, improve renal function, reduce chronic inflammation, reduce lipoprotein, reduce chylomicron, increase postprandial triglycerides, increase very-low-density lipoprotein cholesterol (VLDL-C), and increase free fatty acids.
GIP: Insulin Secretion and Adipose Tissue Metabolism
GIP, secreted by K cells of the duodenum and the proximal part of the small intestine, is the principal incretin hormone in humans, providing most of the incretin effect. GIP receptors (GIPRs) are distributed in the pancreas as well as in extra-pancreatic tissues, such as adipose tissue (both white and brown adipose tissue), the heart, the pituitary, the adrenal cortex, and some areas of the central nervous system (CNS). GIP has long been considered a hormone that promotes obesity; GIP is excessively secreted after nutrient consumption, and it promotes fat deposition in adipose tissue. However, the role of GIP in weight control is not clear. In fact, on the one hand, it has been shown that GIP is involved in fat accumulation, and GIPR-deficient mice are resistant to obesity, but on the other hand, it has been demonstrated that chronic augmented GIP levels in a transgenic mouse model diminish diet-induced obesity as well as increase insulin sensitivity, glucose tolerance, and β-cell function. Interestingly, GIP alone doesn’t suppress appetite or promote weight loss, says Dr. Kumar.But when paired with GLP-1 - as in a dual GIP/GLP-1 agonist medication - GIP gives GLP-1 an extra boost and helps you feel fuller, improving blood sugar control and metabolism. Together, they can lead to greater weight loss for some.Researchers believe that most of the appetite suppression and weight loss come from GLP-1, but GIP enhances or “supercharges” these effects. “Think of it like a battery and a flashlight,” says Kumar.
Clinical Evidence: GLP-1 and GIP Agonists in Weight Management
Clinical evidence highlights the significant impact of GLP-1 and GIP agonists on weight loss, particularly in individuals with type 2 diabetes mellitus (T2DM).
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GLP-1 Receptor Agonists: A Paradigm Shift in Obesity Treatment
With the advent of GLP-1 mimetics like liraglutide and semaglutide, obese individuals now have access to approved alternatives for weight management beyond traditional methods, marking a significant shift in obesity treatment without the prerequisite of diabetes. In clinical trials involving 17,183 patients, 50.2% of participants treated with GLP-1 receptor agonists lost at least 5% of their body weight, and 17.5% achieved a weight loss of 10% or more, both figures being significant compared to a placebo group.
GLP-1/GIP Co-agonists: A New Era in Obesity Treatment
The exploration of GLP-1/GIP co-agonism heralds fewer side effects, suggesting a breakthrough in long-term obesity management. The advent of dual agonists such as tirzepatide underscores a new era in obesity treatment, demonstrating superior efficacy with potentially fewer side effects. Tirzepatide, the first in this class, improves glycemic control by increasing insulin sensitivity and lipid metabolism as well as by reducing body weight. Combining the activation of the two receptors, greater improvement of β-cell function offers more effective treatment of diabetes and obesity with fewer adverse effects than selective GLP-1R agonists.
Tirzepatide: A Dual GIP/GLP-1 Receptor Agonist
To date, tirzepatide, also known as LY3298176, is the only promising dual GIP/GLP-1 receptor agonist. To evaluate the effects of tirzepatide, many studies have been conducted in high-fat diet-fed, obese, insulin-resistant mice. Tirzepatide simultaneously stimulates GIP and GLP-1 receptors, which increases general insulin sensitivity, leading to improved glycemic control and better weight loss compared to GLP-1-RAs. Tirzepatide increases adiponectin and decreases serum alanine aminotransferase and lipoprotein biomarkers. Moreover, branched-chain amino acids (BCAAs) and their catabolic products, which are associated with the risk of obesity, insulin resistance, and T2DM, are significantly reduced by tirzepatide.
From the pharmacological point of view, signaling studies have shown that tirzepatide has mimetic effects of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to promote cAMP generation over β-arrestin recruitment, which is in line with a weaker ability to induce GLP-1 receptor internalization compared to GLP-1.
In a multicenter, randomized, double-blind, parallel-arm, phase 1 study, Heise et al. demonstrated that the administration of tirzepatide (15 mg) significantly improves the clamp disposition index from baseline to week 28 of treatment compared to semaglutide or a placebo; moreover, tirzepatide significantly reduces glucose excursions compared to a placebo, suggesting that the effect of tirzepatide is related to improvements in β-cell function, insulin sensitivity, and glucagon secretion (40). Furthermore, co-treatment with a GLP-1R agonist and a GIPR agonist results in more insulin sensitivity, glucose reduction, food intake reduction, and body weight reduction than either agonist alone in obese mice with type 2 diabetes (33).
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Tirzepatide, as highlighted in murine models, increases insulin sensitivity in a weight-dependent and weight-independent (through action on GIPR) manner, thereby stimulating metabolic pathways that oxidate glucose, lipids, and BCAAs. Thus, this mechanism, which avoids excessive nutrients, achieves metabolically active organs with a gain in insulin sensitivity and weight loss, providing long-lasting effects, unlike drugs, that act only in a weight-dependent manner (23). Recent data have indicated that treatment with tirzepatide stimulates the catabolism of BCAAs/branched-chain ketoacids (BCKAs) in brown adipose tissue (BAT). However, tirzepatide increases the level of amino acids in BAT to a level similar to that after cold exposure.
GIP Receptor Agonism and Antagonism: A Complex Picture
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.
GIPR Expression in Various Tissues
The GIPR is expressed in select cell types throughout the body, many of which exert direct or indirect control over body weight. There is a consensus for many of the reported GIPR + tissues, supported by detailed gene expression analysis and functional data. However, some tissues reported to be GIPR + are questionable, with mixed degrees of support. Some of the difficulty in assessing whether a particular cell type expresses a functional receptor is the lack of quality reagents needed to ascertain the expression of GIPR.
Pancreatic islets robustly express the GIPR, and this tissue is commonly used as a positive control for expression levels. RNA analysis of mouse islets shows similar expression levels among α, β, and δ cells, aligning with reports that GIPR agonists increase glucagon, insulin, and somatostatin secretion in rodents and humans. Single-cell RNA sequencing (scRNAseq) of human islets also supports GIPR expression in α, β, and δ cells along with similar expression levels in γ cells.
The GIPR has been identified in multiple adipose tissue depots. Gipr/GIPR levels are detectable in rodent and human white adipose tissue (WAT) samples, but the cellular source of this signal among heterogenous populations of cells within this tissue is unclear. Much of the literature investigating the role of GIPR in “white adipocytes” was derived from rodent and human differentiated cell lines originating from progenitor cells, for example, 3T3-L1 cells. The expression of Gipr/GIPR is absent in precursor cells and robustly increases upon chemical induction of differentiation. The extent to which this in vitro process replicates the expression levels of primary white adipocytes is known.
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There is widespread expression of Gipr in the rodent brain. Gipr expression has been reported in the cerebral cortex, hippocampus, olfactory bulb, brain stem, and cerebellum in rats, which aligns with regions identified by radiolabeled GIP-binding assays, in situ hybridization, and qPCR analysis.
The Role of GIPR in Diet-Induced Obesity
The first observation provoking interest in how GIP might regulate body weight in response to overnutrition came from global germ-line deletion of Gipr in mice (Gipr−/−). When fed a standard rodent diet, body weight gain was the same between wild-type (WT) and Gipr−/− mice; however, the knockout mice were robustly protected from weight gain when fed a high-fat diet. This protection against high-fat diet-induced obesity in Gipr−/− mice was replicated by multiple labs in subsequent studies. In addition, crossing the Gipr−/− with leptin-deficient ob/ob mice conferred partial protection against weight gain.
The decreased weight gain exhibited by Gipr−/− fed a high-fat diet was attributed to decreased fat mass in some but not all studies. How global deletion of the GIPR confers protection against diet-induced obesity remains unclear and debated. Modest decreases in food intake in Gipr−/− mice have been reported; however, these differences disappear when expressed relative to body weight, and other studies report no difference in food intake. Energy expenditure measured by indirect calorimetry was slightly elevated in Gipr−/− mice relative to diet-matched control mice. However, increased energy expenditure of a similar magnitude was also noted in Gipr−/− mice fed standard rodent chow, a condition in which body weight was comparable to diet-matched control mice. Whether this modest increase in energy expenditure contributes to protection against weight gain in high-fat fed Gipr−/− mice but not mice fed a standard diet remains unresolved. It has been reported that Gipr−/− mice use lipids as a preferred energy substrate.
A common hypothesis to explain the protective phenotype of Gipr−/− mice is that loss of GIPR activity in white adipose tissue limits lipogenesis. Most support for this hypothesis comes from work in 3T3-L1 adipocytes, where GIP stimulates glucose uptake and lipoprotein lipase activity. The majority of these experiments utilized supraphysiological concentrations of insulin (often 1 nM) in combination with GIPR agonism (also often used at high concentrations, for example, 100 nM), as GIPR agonism alone fails to enhance lipogenesis. In rat adipocytes, GIP increased free fatty acid re-esterification to produce a net decrease in lipid efflux and attenuated the lipolytic response to isoproterenol. Chronic GIPR agonism led to impaired insulin-stimulated glucose uptake in differentiated human adipocytes, which would be expected to impair lipogenesis. However, in contrast to these experiments, GIP was reported to stimulate lipolysis in isolated rodent adipocytes, differentiated human adipocytes, and studies of human subjects.
Obesity and Co-morbidities
The World Health Organization (WHO) defines obesity as abnormal or excessive fat accumulation that presents a risk to health. Obesity is characterized by a body mass index (BMI) greater than 30 kg/m2, and it has rapidly become a global disease, with over four million deaths each year (1). The pathogenesis of obesity is multifaceted with environmental, socio-cultural, physiological, medical, behavioral, genetic, and epigenetic factors (2). Obesity is correlated with a wide variety of chronic diseases, including tumors, hypertension, type 2 diabetes mellitus (T2DM), cerebrovascular diseases, and chronic kidney disease (3). Thus, it is imperative to promote weight loss to reduce severe complications (8).
Obesity is distinguished by excess adiposity distributed to many body compartments. The increase of adiposity in pharyngeal soft tissue causes blocked airways during sleep, triggering obstructive sleep apnea; moreover, it causes both osteoarthritis, due to increased mechanical loading on the joints, and gastroesophageal reflux disease, due to an increase in intra-abdominal pressure. The obesity-related proinflammatory state with an increase in cytokines prompts insulin resistance, and together with insulin secretion that increases linearly with the BMI, supports dyslipidemia and T2DM. This obesity-induced chronic inflammation plays an endorsing role in cancer progression due to its promotion of a permissive microenvironment for neoplastic transformation. Furthermore, liposomes augment in hepatocytes that evolve in non-alcoholic fatty liver disease, steatohepatitis, and cirrhosis. Another consequence of obesity is chronic overactivity of the sympathetic nervous system that, together with the previously described consequences of chronic obesity, induces hypertension and increases the risk of heart disease, stroke, and chronic kidney diseases.
Traditional vs. Incretin-Based Therapies for Obesity
The cornerstone of obesity management comprises behavioral therapy (diet and lifestyle modifications), drugs, and bariatric surgery. Drug therapies, which should be considered for patients with a BMI of ≥30 kg/m2 and a BMI of ≥27 kg/m2 with weight-related comorbidities, stimulate satiety, reduce hunger, and/or reduce fat absorption or catabolism (9). Because the pathophysiology of obesity is complex, single-targeting agents have limited efficacy, suggesting that drug therapies that target multiple mechanisms are more effective than single-targeting agents.
Among the medications approved for the long-term management of obesity, incretins represent appealing targets for inducing weight loss and preventing metabolic disorders. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two hormones responsible for the amplification of insulin secretion after nutrient consumption, and they have different actions (11). GLP-1 receptor agonist (GLP-1-RA) helps weight loss by suppressing appetite within the hypothalamus and inducing peripheral satiety by reducing gastric emptying, thus diminishing calorie intake (12). Similarly, GIP regulates energy balance through cell surface receptor signaling in adipose tissue and the brain (13).
Mechanisms Underlying GLP-1/GIP Synergism
Though the exact mechanisms underlying GLP-1/GIP synergism are unclear, some hypotheses have suggested that GIP operates directly via the CNS by reducing food intake, increasing the anorexigenic action of GLP-1, or enhancing tolerability to GLP-1R agonists (13). The brain acts on both energy intake and expenditure, and control of energy balance is achieved by a complex mechanism involving the hypothalamus, hindbrain, amygdala, prefrontal cortex, and hippocampus. The ARC, a key site of the hypothalamus, receives direct signals from the periphery, and it contains both orexigenic neurons expressing Agouti-related peptide (AgRP)/NPY and anorexigenic neurons expressing POMC (27).