What is the role of Glucagon-like peptide-1 (GLP-1) analogues, such as liraglutide (Victoza) or semaglutide (Ozempic), on ghrelin, leptin, and adipokines in patients with type 2 diabetes or obesity?

Role of GLP-1 Analogues on Ghrelin, Leptin, and Adipokines

GLP-1 receptor agonists like liraglutide and semaglutide decrease circulating leptin levels, increase GIP levels, and modestly increase adipokines like visfatin and resistin, though these hormonal changes appear secondary to their primary mechanisms of appetite suppression through central nervous system pathways rather than direct effects on these hormones. 1, 2

Direct Effects on Leptin

GLP-1 analogues consistently reduce leptin levels in patients with type 2 diabetes and obesity:

• Liraglutide 1.8mg daily for 17 days significantly decreased leptin levels compared to placebo in a randomized, double-blind crossover trial, even before any weight loss occurred 2
• After 14 weeks of liraglutide treatment (up to 1.8mg/day), patients showed improved insulin sensitivity (HOMA-IR decreased from 8.4 to 4.6 mol·mIU/L²) alongside these leptin reductions 1
• The leptin decrease appears to be an early effect that precedes weight loss, suggesting a direct metabolic influence rather than simply reflecting reduced adipose tissue 2

Critical nuance: The decrease in leptin was associated with increased activation in reward-related brain regions (midbrain, precuneus, DLPFC) when viewing food cues, potentially representing a compensatory mechanism that could limit long-term weight loss efficacy 2

Effects on Ghrelin

The evidence does not demonstrate significant direct effects of GLP-1 analogues on ghrelin levels:

• Current research has not established meaningful changes in circulating ghrelin with liraglutide or semaglutide treatment 2
• The primary appetite-suppressing mechanism operates through GLP-1 receptors in the hypothalamus and brainstem, inducing meal termination through parabrachial neurons and vagal nerve signaling, rather than through ghrelin modulation 3

Impact on Adipokines

GLP-1 receptor agonists produce modest but statistically significant increases in certain adipokines:

• Liraglutide 1.8mg daily for 14 weeks significantly increased visfatin levels (from 6.3 to 6.8 ng/ml) and resistin levels (from 3.6 to 4.3 ng/ml) in overweight/obese patients with type 2 diabetes 1
• Baseline visfatin levels were negatively correlated with fasting plasma glucose (r=-0.360, p<0.05), suggesting these adipokines may play a role in treatment response 1
• Adiponectin levels were measured but showed no significant changes with liraglutide treatment 1

GIP (Glucose-Dependent Insulinotropic Polypeptide) Changes

• Liraglutide treatment significantly increased circulating GIP levels (p<0.03) after 17 days, which is particularly relevant given that tirzepatide combines GLP-1 and GIP receptor agonism 2
• Increased GIP levels were associated with deactivation of the attention- and reward-related insula on fMRI when viewing food cues, suggesting a role in altered food perception 2

Clinical Implications and Mechanisms

The hormonal changes with GLP-1 analogues appear to be secondary effects rather than primary mechanisms of action:

• The weight loss and metabolic benefits occur primarily through delayed gastric emptying, central appetite suppression via hypothalamic GLP-1 receptors, and vagal nerve signaling 3, 4
• Pro-inflammatory cytokines (IL-6, TNF-α) were measured but showed no significant changes, suggesting the metabolic benefits occur through pathways independent of systemic inflammation 1
• The decrease in leptin despite ongoing weight loss may represent a compensatory mechanism that could explain why weight loss plateaus over time, potentially supporting the rationale for combination therapies 2

Practical Considerations

For patients on liraglutide or semaglutide:

• Do not expect ghrelin suppression as a mechanism of action—appetite reduction occurs through central GLP-1 receptor activation 3, 2
• The leptin decrease occurs early (within 17 days) and precedes significant weight loss, making it a potential early biomarker of treatment response 2
• Tirzepatide's dual GIP/GLP-1 mechanism may provide additional metabolic advantages given that GLP-1 analogues increase endogenous GIP levels 2, 3
• The modest increases in visfatin and resistin have unclear clinical significance but may contribute to improved insulin sensitivity 1

Common pitfall: Attributing GLP-1 analogue efficacy primarily to hormonal changes in leptin, ghrelin, or adipokines—the dominant mechanisms are central nervous system appetite suppression and delayed gastric emptying, with these hormonal changes representing secondary metabolic adaptations 3, 4, 2