In recent years, GLP-1 receptor agonists (GLP-1RAs) have shown remarkable efficacy in weight loss. It is often claimed that these drugs not only produce excellent weight loss results but also primarily reduce visceral adipose tissue (VAT) rather than subcutaneous adipose tissue (SAT). If this is indeed the case, what are the underlying biological mechanisms? This article will systematically review the relevant evidence to serve as a reference for clinicians and researchers.
Clinical Evidence
A rat study by Zhao L et al. (2019) provided the most direct insights into the mechanism of action. Using MRI and isotope tracing techniques, the study found that treatment with liraglutide resulted in a significant reduction in visceral fat and a relative increase in subcutaneous fat [1].
A meta-analysis by Liu et al. (2022), which included 10 RCTs involving a total of 924 patients with type 2 diabetes, confirmed that GLP-1 receptor agonists (GLP-1RAs) result in a greater relative reduction in visceral adipose tissue (VAT) than in subcutaneous adipose tissue (SAT), leading to a significant improvement in the VAT/SAT ratio [2].
In the STEP 1 trial, treatment with semaglutide 2.4 mg for 68 weeks resulted in a 13.5 cm reduction in waist circumference (compared to 4.1 cm with placebo), and MRI/CT scans confirmed a significant reduction in visceral fat [3].
The SURPASS-3 MRI substudy showed that treatment with tirzopentide 15 mg for 52 weeks reduced VAT by 1.65 L (a reduction of approximately 24%), and the VAT/ASAT ratio decreased significantly, suggesting a redistribution of fat from visceral to subcutaneous tissue [4].
The SURMOUNT-1 DXA substudy further confirmed that telipepetide reduced visceral fat mass by 40.1% (compared to 7.3% with placebo), with fat mass reduction accounting for approximately 75% of total weight loss [5].
Molecular Mechanisms
- Anatomical Differences in Receptor Distribution
Vendrell et al. (2011) demonstrated that in patients with morbid obesity and severe insulin resistance, GLP-1R mRNA and protein expression in VAT was significantly higher than in SAT [6]. This difference is particularly pronounced in individuals with severe insulin resistance, providing a basis for the preferential response of VAT.
The distribution of GIPR further reinforces the VAT preference of dual-target drugs. GIPR expression in VAT is significantly higher than in SAT (approximately 3.2-fold) and is highly correlated with fatty acid oxidation genes [7]. This provides an additional basis for the VAT targeting of tirzopentide.
- Differential Regulation of Lipolysis and Lipogenesis
GLP-1 enhances lipolysis by activating the GLP-1 receptor (GLP-1R) via the cAMP/PKA signaling pathway. In VAT, due to higher GLP-1R expression, theoretically, the same plasma concentration of GLP-1 can produce a stronger cAMP-PKA activation effect, thereby phosphorylating and activating hormone-sensitive lipase (HSL) and ATGL to promote triglyceride breakdown. However, this effect has not yet been experimentally verified.
GLP-1RA downregulates key enzymes and transcription factors involved in lipogenesis (PPARγ, C/EBPβ/δ) in VAT, whereas in SAT, it may upregulate lipogenesis-related genes, promoting “healthy” fat storage [1].
- Tissue-Specificity of Browning Remodeling
Liraglutide induces browning remodeling in subcutaneous fat (upregulation of UCP1) but does not induce browning in visceral fat [1]. This combination of “subcutaneous browning and visceral lipolysis” results in a healthy redistribution of fat.
- Improving the Inflammatory Microenvironment
GLP-1 RAs help break the vicious cycle of “adipocyte dysfunction–inflammation–insulin resistance” by suppressing inflammatory responses in visceral adipose tissue and promoting the polarization of macrophages toward the M2 anti-inflammatory phenotype, thereby improving the adipose tissue microenvironment [8].
- Central-Peripheral Coordination
GLP-1 suppresses food intake by acting on the central nervous system. During acute energy demands (such as short-term fasting or exercise), visceral fat—due to its higher density of sympathetic innervation and β-adrenergic receptor expression—exhibits greater sensitivity to lipolysis and is preferentially mobilized to provide free fatty acids. However, this preference diminishes as the duration of energy deprivation increases [9].
Key Distinctions
“Focusing on reducing visceral fat” does not mean that subcutaneous fat is unaffected. In fact, both types of fat are reduced, but the relative reduction in VAT is greater; improvement in the VAT/SAT ratio is the key indicator. Dieting alone reduces VAT and SAT in roughly equal proportions, whereas GLP-1 receptor agonists (GLP-1RAs) possess tissue-specific metabolic regulatory capabilities. Furthermore, upregulation of GLP-1R expression in VAT is primarily observed in patients with morbid obesity and severe insulin resistance [6], suggesting that those at the highest metabolic risk derive the greatest benefit.
Summary
Visceral fat is an independent risk factor for metabolic syndrome, type 2 diabetes, and cardiovascular disease. Current research has found that GLP-1 agonists primarily target visceral fat reduction, which may result from a combination of factors, including differences in receptor distribution, variations in the intensity of signaling pathway activation, differences in the direction of lipid metabolism regulation, improvements in the inflammatory microenvironment, and central-peripheral synergistic effects.
References
[1] Zhao L, et al. The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution. J Endocrinol. 2019;240(2):273-284.
[2] Liu X, et al. Effect of GLP-1 receptor agonists on visceral and subcutaneous adipose tissue in adults with type 2 diabetes: a meta-analysis. Front Endocrinol. 2022;13:1020509.
[3] Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
[4] Gastaldelli A, et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI). Lancet Diabetes Endocrinol. 2022;10(6):393-406.
[5] Rosenstock J, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
[6] Vendrell J, et al. Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology. 2011;152(11):4072-4079.
[7] Samms RJ, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021;131(12):e146353.
[8] Sztanek, F, et al. New developments in pharmacological treatment of obesity and type 2 diabetes—Beyond and within GLP-1 receptor agonists. Biomedicines, 12 (6), 1320.
[9] Tang HN, et al. Plasticity of adipose tissue in response to fasting and refeeding in male mice. Nutr Metab (Lond). 2017 Jan 5;14:3.