What is the role of ghrelin and Glucagon-like peptide-1 (GLP-1) in weight and hunger control?

Ghrelin and GLP-1 in Weight and Hunger Control

Opposing Roles in Appetite Regulation

Ghrelin is the only known circulating orexigenic hormone that stimulates appetite and increases food intake, while GLP-1 is an incretin hormone that suppresses appetite, delays gastric emptying, and promotes satiety—making them key opposing regulators of hunger and body weight. 1

Ghrelin: The Hunger Hormone

Mechanism and Secretion Pattern:

• Ghrelin is secreted primarily from the gastrointestinal tract (stomach) and is the only enteroendocrine hormone that increases appetite 1
• Ghrelin levels peak 1-2 hours before meals (preprandially) and decline sharply after food ingestion 2
• The hormone stimulates food intake, promotes adipogenesis, and increases gastrointestinal motility 2

Relationship with Body Weight:

• Plasma ghrelin concentrations are inversely related to BMI—reduced in obesity and insulin resistance 1
• There is an inverse relationship between ghrelin levels and body weight, with lower levels seen in obese populations 1
• Ghrelin blood concentration is reduced in massive obesity and increased in conditions of anorexia or starvation 2

GLP-1: The Satiety Hormone

Mechanism and Secretion Pattern:

• GLP-1 is secreted from the gastrointestinal tract and decreases appetite through activation of GLP-1 receptors in the hypothalamus and brainstem 3
• GLP-1 regulates body weight by diminishing appetite and delaying gastric emptying in concert with other satiety hormones like PYY and CCK 1, 3
• The mechanism involves both delayed gastric emptying and direct central nervous system effects that reduce caloric intake 3

Pharmacological Applications:

• FDA-approved GLP-1 receptor agonists for weight loss include liraglutide (3.0 mg daily) and semaglutide (2.4 mg weekly) for individuals with BMI ≥30 or BMI ≥27 with weight-related comorbidities 3
• Semaglutide demonstrates superior weight loss with mean reduction of 14.9% from baseline in non-diabetic patients with obesity 3
• Tirzepatide (dual GIP/GLP-1 receptor agonist) shows even greater efficacy with 15-20.9% weight loss at higher doses 3

Interaction Between Ghrelin and GLP-1

The relationship between these hormones is complex and context-dependent:

• Contradictory evidence exists regarding direct interaction: One study suggests ghrelin enhances glucose-stimulated GLP-1 release and improves glucose tolerance when administered before oral glucose 4, while a more recent high-quality study demonstrates that ghrelin does not directly stimulate GLP-1 secretion in humans or perfused mouse intestine 5
• GLP-1 administration at supraphysiological levels reduces ghrelin levels in the late postprandial period, likely through its insulinotropic action and increased insulin secretion 6
• The ghrelin receptor is undetectable in mouse L-cells and marginal in human L-cells, suggesting no direct interaction at the cellular level 5

Clinical Implications for Weight Management

GLP-1 Receptor Agonist Therapy:

• Liraglutide mechanism: Activates GLP-1 receptors leading to insulin release in the presence of elevated glucose, decreases glucagon secretion, and delays gastric emptying 7
• Semaglutide mechanism: Similar to liraglutide, with longer half-life allowing once-weekly dosing and greater weight loss efficacy 8
• Common adverse effects include gastrointestinal symptoms (nausea, vomiting, diarrhea) that may limit tolerability 3
• Weight regain occurs after discontinuation, indicating long-term therapy is necessary for sustained weight loss 3

Important Caveats:

• In obesity and insulin resistance states, the incretin effect is decreased due to increased degradation of GLP-1 by DPP-4 enzyme 1
• Tachyphylaxis can develop with long-acting GLP-1 receptor agonists, reducing effects on gastric emptying and satiety signals 3
• Patients with diabetes typically experience less weight loss (4-6.2%) compared to non-diabetic patients (6.1-17.4%) when using GLP-1 receptor agonists 3, 9

Dysregulation in Disease States

In Type 1 Diabetes:

• Ghrelin levels are reduced in both adults and children with T1D 1
• GLP-1 levels remain similar to healthy controls, with no difference in postmeal GLP-1 rise 1, 9
• The most severe defects in food intake regulation are due to impairments in pancreatic hormone release (insulin, glucagon, amylin) rather than GLP-1 dysfunction 1

In Obesity:

• Defective communication circuits between gut and brain are implicated in obesity pathogenesis 1
• The incretin effect is diminished in the proinflammatory, insulin-resistant state common in obesity 1