Metabolic peptide mechanisms

GLP-1R

GLP-1 receptor signalling

GLP-1 is a gut hormone released after eating. Drugs that activate the GLP-1 receptor act on the pancreas (to release insulin in a glucose-dependent way), the brain (to reduce appetite and food reward) and the stomach (to slow emptying). The effect on body weight comes mainly from reduced appetite over time.

GIPR

GIP receptor signalling

GIP is the other major incretin hormone. Its role in body weight is more complex than GLP-1's: depending on dosing, duration and combination, GIP receptor activity has been argued to enhance or constrain weight effects. The clinical fact is that adding GIP agonism to GLP-1 agonism (as in tirzepatide) produces larger trial-measured weight reductions in studied populations than GLP-1 alone.

GCGR

Glucagon receptor agonism (in incretin combinations)

Glucagon usually raises blood sugar. In small, carefully balanced doses combined with strong GLP-1 (and sometimes GIP) agonism, glucagon receptor agonism appears to increase energy expenditure, drive hepatic fat oxidation and contribute to weight reduction without producing the hyperglycaemia that uncontrolled glucagon agonism would cause.

Gastric emptying and tachyphylaxis

GLP-1 receptor agonists slow gastric emptying, especially early after dose escalation. With ongoing dosing the gastric-emptying effect diminishes (tachyphylaxis), while appetite suppression in the brain remains. This is why early GI side effects often improve over time even as weight reduction continues.

Central appetite regulation

Appetite is regulated by brain circuits that integrate gut and fat-tissue signals. GLP-1 receptor agonists act on these circuits to reduce subjective hunger and the amount eaten at meals, which is the dominant explanation for chronic weight reduction in clinical trials.

Food reward and hedonic eating

Eating is partly driven by reward — wanting and liking certain foods. GLP-1 receptor agonists appear to reduce the hedonic pull of palatable foods in addition to reducing hunger. This may explain reports of reduced cravings and altered preferences during therapy.

Adipose tissue remodelling

Weight loss with incretin therapy is not just generic fat loss. Imaging studies (DXA, MRI) show preferential reduction of visceral adipose tissue and liver fat, and changes in adipose inflammation markers. These tissue-level changes likely contribute to the cardiometabolic effects observed in trials.

Lean mass preservation in incretin therapy

When body weight falls, some lean mass is normally lost alongside fat. The clinical question is whether the proportion of lean-mass loss with incretin therapy is greater than with comparable diet-based weight loss, and how to support muscle and bone during therapy.

Thermogenesis and energy expenditure

Most of the weight-loss effect of GLP-1 medicines comes from reduced food intake. With glucagon-receptor agonism (in dual or triple agonists), there is also evidence for an increase in energy expenditure, which adds to the calorie-deficit driver of weight loss.

Pancreatic β-cell effects

GLP-1 and GIP both enhance the pancreas's ability to release insulin when blood glucose rises. Because the effect is glucose-dependent, it does not typically cause hypoglycaemia on its own — though combined use with insulin or sulfonylureas changes that risk.

Incretin effects on the liver (MASLD/MASH)

Excess fat in the liver — MASLD / MASH — is closely tied to obesity and insulin resistance. Incretin therapy reduces liver fat, mainly through weight loss for GLP-1 mono-agonists; glucagon-receptor-containing combinations may add direct hepatic effects.

GH axis and visceral adiposity

The growth-hormone axis influences fat distribution, especially visceral fat. Tesamorelin is licensed in the US (Egrifta) for HIV-associated lipodystrophy and is the main human-licensed molecule acting via this pathway. CJC-1295, ipamorelin and similar growth-hormone-secretagogue research compounds are not licensed for human therapeutic use in the UK.

GHRH analogues vs GHS-R1a (ghrelin-mimetic) secretagogues

Two different ways to stimulate the body's own growth-hormone output. GHRH analogues like tesamorelin mimic the natural releaser; GHS-R1a agonists like ipamorelin mimic ghrelin. Both raise GH, but with different physiology and safety profiles.

Lipolysis vs lipogenesis (lipolytic peptide fragments)

Some research peptides claim to push fat tissue toward burning stored fat rather than storing more. In humans, the evidence base for these fragments has not matured into licensed medicines and clinical effect sizes have not been established with rigour.