Gastrointestinal Hormones' Functions in Obesity
Food ingestion triggers several physiological responses in the digestive system, including the release of gastrointestinal hormones from enteroendocrine cells that are involved in appetite signalling. Disturbed regulation of gut hormone release may affect energy homeostasis and contribute to obesity.
2. Strategies for the Management of Obesity: Role of Gut Hormones
2.1. Diet-Induced Weight Loss
2.2. Roux-en-Y Gastric Bypass Surgery Restores the Gut Hormone Balance
Figure 1. An overview of the mechanisms and the differences in fasting (GHRL, MLN) and postprandial (CCK, GLP-1, PYY) gut hormone plasma levels in obese/type 2 diabetes patients before and after a Roux-en-Y gastric bypass (RYGB) surgery. Abbreviations: GHRL: Ghrelin; MLN: Motilin; CCK: Cholecystokinin; GLP-1: glucagon-like peptide 1; peptide YY.
2.3. Combination Therapy
GGLP-1R agonists are used widely to treat T2DM. Liraglutide, which is administered once a day, was until now the only GLP-1 receptor (GLP-1R) agonist to be approved for weight management . Recently, Semaglutide, a long acting GLP-1R agonist, has proven to be effective in weight management as an adjunct to lifestyle by inducing 14.9% weight loss from baseline in overweight and obese individuals . Combined agonism, mostly by combining GLP-1 analogues with other food intake-inhibiting and/or glucose-lowering hormones, may cause a synergistic pharmacological action in obese individuals and patients with T2DM. Therefore, combination therapy is currently considered as the way to go to mimic the beneficial effects of RYGB surgery in a non-surgical manner . Table 2 gives an overview of several combinations with GLP-1R analogues that are currently in clinical trial.
|Combination Therapy||Physiological Effect||Drug Candidates|
Decrease food intake
|Tirzepatide||Eli Lilly||Phase II|
|GLP-1–GCG||Insulinotropic effect cardiovascular protection
Decrease food intake
Increase energy expenditure
|Efinopegdutide||Hanmi Pharmaceuticals||Phase II|
Increase energy expenditure
Decrease food intake
|HM15211||Hanmi Pharmacueticals||Phase II|
Glucagon-like-peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon (GCG).
2.3.1. GLP-1 and GIPGlucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is secreted by K-cells in response to nutrients to stimulate insulin secretion through activation of GIP receptors on pancreatic beta cells, and acts as a blood glucose stabilising hormone by regulating insulin and glucagon secretion . GIP also exerts direct actions on lipid metabolism, promoting lipogenesis and weight gain, and GIPR agonists have been demonstrated to exacerbate the postprandial glucagon excursion in individuals with T2DM . Therefore, GIP receptor (GIPR) antagonists were initially developed to induce weight loss and to control glycaemia levels in obesity and individuals with T2DM . Even though individuals with T2DM have a decreased insulinotropic effect of GIP, due to impaired responsiveness by beta cells, the loss of GIP has been shown to enhance GLP-1R activity . Evidence suggests that GIPR agonism can also positively impact body weight. A recent study showed that injection of a peripherally long acting, selective mouse GIPR agonist in DIO mice, lowered body weight due to reduced food intake . Therefore, dual agonism of GLP-1R, which exerts glycaemic control, and GIPR represents a strategy in treating obesity and T2DM. Coadministration of the selective GIP receptor agonist, ZP4165, together with the GLP-1R agonist, liraglutide, in DIO mice resulted in superior body weight loss and improved blood glucose and plasma cholesterol levels . Currently, tirzepatide, a dual-incretin peptide from Eli Lilly, has reached multi-dose clinical trials and shows promise in the treatment of obesity and T2DM .
2.3.2. GLP-1 and GCG
2.3.3. GLP-1 and PYY3-36
The combination of GLP-1 analogue with PYY3-36 mainly has a role in body weight management. Co-infusion of PYY3-36 and GLP-1 reduced energy intake by 30% compared to placebo in overweight men, which was not achieved when a mono-infusion was administered of PYY3-36 or GLP-1 . In addition, co-administration of PYY3-36 with oxyntomodulin reduced energy intake by 42.7% in overweight and obese volunteers, and the effect was more pronounced than when either hormone was infused separately . No drugs are yet in clinical trials for combinations with PYY3-36.
2.3.4. GLP-1, GCG and GIP
Gut hormones are important players in the regulation of appetite. Obesity has a clear impact on fasted and meal-related fluctuations in gut hormone release but the effect on some hormones remains controversial. The mechanisms involved are complex and multifactorial, relating to changes in the number/content of EECs, effect of age and gender, alterations in nutrients’ sensing mechanisms that regulate postprandial responses, alterations in diurnal fluctuations, and may also involve alterations in the central responsiveness to gut hormones. Further exploration of the crosstalk between the gut microbiome and EECs is of interest. Restoring the disordered gut hormone balance in obesity by targeting nutrient sensors in selective regions of the gut or by combined administration of gut peptide mimetics represent a major potential therapeutic targets to improve the prevention and management of obesity.
The entry is from 10.3390/nu13061839
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