By Cocer Peptides 
27 days ago
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Overview
HIV infection and antiretroviral therapy (ART)-induced fat metabolism abnormalities pose serious challenges to the health and quality of life of HIV patients. These abnormalities manifest in various forms, such as lipoatrophy and lipohypertrophy, with excessive accumulation of visceral adipose tissue (VAT) being particularly prominent. The increase in VAT not only affects patients' physical appearance but is also closely associated with a range of severe metabolic complications, including cardiovascular disease, insulin resistance, and non-alcoholic fatty liver disease (NAFLD), posing a serious threat to patients' long-term survival and health status.
Tesamoreli, a synthetic growth hormone-releasing hormone (GHRH) analog, offers new hope for the treatment of fat metabolism abnormalities in HIV patients. It specifically binds to GHRH receptors in the anterior pituitary gland, effectively stimulating the synthesis and release of endogenous growth hormone (GH). GH plays a crucial role in regulating fat metabolism in the human body, promoting lipolysis, enhancing fatty acid oxidation, and regulating the expression of genes related to lipid metabolism, thereby exerting a positive influence on fat metabolism. This unique mechanism of action enables Tesamoreli to help improve fat metabolism disorders in HIV patients.
Figure 1 Analysis Schema. A total of 9 plasma proteins were examined, corresponding to top leading edge genes within hepatic gene pathways differentially modulated by tesamorelin.
Mechanism of Action of Tesamoreli on Fat Metabolism in HIV
Patients
Regulation of the Growth Hormone-Insulin-Like Growth Factor Axis
Tesamoreli binds to the GHRH receptor on the cell membrane of the anterior pituitary gland, activating receptor-associated signaling pathways such as the JAK-STAT signaling pathway. This activation process promotes the synthesis and release of growth hormone (GH) by the anterior pituitary gland. After entering the bloodstream, reaches target organs such as the liver, stimulating the liver to synthesize and secrete insulin-like growth factor-1 (IGF-1). IGF-1 serves as a key mediator of GH's metabolic effects and plays a crucial role in fat metabolism. IGF-1 can activate the PI3K-AKT signaling pathway, inhibit adipocyte apoptosis, and maintain normal adipocyte function. It also promotes the uptake and oxidation of fatty acids by adipocytes, reducing fat accumulation within cells. In HIV patients, the function of the growth hormone-insulin-like growth factor axis is often impaired due to the disease itself and the effects of antiretroviral therapy (ART). Tesamoreli can activate this axis to restore its normal fat metabolism regulatory function.
Direct effects on adipocyte metabolism
Promoting lipolysis: Tesamoreli can upregulate the expression and activity of hormone-sensitive lipase (HSL) in adipocytes. HSL is a key enzyme in lipolysis, catalyzing the hydrolysis of triglycerides into glycerol and fatty acids, thereby promoting the catabolic metabolism of fat. In vitro, adding Tesamoreli to cultured adipocytes significantly enhances HSL activity and markedly increases fatty acid release. Tesamoreli can also indirectly activate HSL by regulating the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway, further promoting lipolysis. In HIV patients, this lipolysis-promoting effect helps reduce excessive fat accumulation, particularly visceral fat reduction, thereby improving abnormal fat distribution in patients.
Regulation of fatty acid oxidation: Tesamoreli enhances the activity of key enzymes involved in fatty acid oxidation within adipocytes, such as carnitine palmitoyltransferase 1 (CPT1). CPT1 is the rate-limiting enzyme for fatty acid entry into mitochondria for β-oxidation, and its enhanced activity promotes the oxidative breakdown of fatty acids within mitochondria, providing energy for cells. Tesamoreli can also upregulate the expression of other enzymes and transporters involved in fatty acid β-oxidation, such as acetyl-CoA carboxylase 2 (ACC2) and fatty acid transporter 1 (FATP1), further optimizing the fatty acid oxidation metabolic process. By promoting fatty acid oxidation, Tesamoreli can reduce fat storage within cells and improve lipid metabolism disorders in HIV patients.
Regulation of lipid metabolism-related gene expression
Influencing adipogenesis-related genes: Tesamoreli can inhibit the expression of adipogenesis-related genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). PPARγ is a key transcription factor in adipocyte differentiation and adipogenesis, promoting the differentiation of fibroblasts into mature adipocytes, and induces the expression of a series of adipogenesis-related genes, such as fatty acid-binding protein 4 (FABP4) and fatty acid synthase (FAS). C/EBPα also plays a crucial role in adipocyte differentiation and adipogenesis. By inhibiting the expression of PPARγ and C/EBPα, Tesamoreli reduces adipocyte differentiation and adipogenesis, thereby decreasing fat accumulation in the body. In HIV patients, this regulatory effect on adipogenesis-related genes helps correct the excessive fat production caused by abnormal fat metabolism.
Figure 2 Relationship of Changes in Plasma VEGFA and CSF1 with Change in NAS Score in Tesamoreli-Treated Participants.
Regulation of lipid transport and metabolism genes: Tesamoreli can regulate the expression of genes related to lipid transport and metabolism, such as members of the apolipoprotein (Apo) family. ApoB is the primary apolipoprotein of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and its expression levels are closely correlated with the levels of VLDL and LDL in plasma. Tesamoreli can reduce ApoB expression, reduce the synthesis and secretion of VLDL and LDL, thereby lowering plasma levels of atherogenic lipoproteins. Additionally, Tesamoreli can upregulate the expression of ApoA-I, the primary apolipoprotein of high-density lipoprotein (HDL). Increased ApoA-I expression helps elevate HDL levels, promote cholesterol reverse transport, and reduce the risk of cardiovascular disease. In HIV patients, where lipid metabolism disorders often accompany lipid metabolism abnormalities, Tesamoreli's regulatory effects on lipid transport and metabolism genes can help improve patients' lipid profiles.
Specific Effects of Tesamoreli on Lipid Metabolism in HIV Patients
Reducing Visceral Adipose Tissue (VAT)
Tesamoreli significantly reduces VAT in HIV patients. In a Phase III clinical trial involving HIV patients, participants were randomly assigned to receive either 2 mg of Tesamoreli daily or a placebo for 26 weeks. In the Tesamoreli treatment group, patients exhibited a significant reduction in VAT, and this reduction was observed across patients with different baseline characteristics (e.g., presence or absence of back-neck fat). For Tesamoreli responders (defined as patients with at least an 8% reduction in VAT and who adhered to treatment), VAT decreased significantly regardless of the presence of neck and back fat, and there was no statistically significant difference between the two groups (P = 0.657). This suggests that Tesamoreli has broad efficacy in reducing VAT in HIV patients, independent of the presence of back-neck fat. The reduction in VAT not only improves patients' physical appearance but more importantly reduces the risk of VAT-related metabolic complications, such as cardiovascular disease and insulin resistance.
Improving liver fat metabolism
Reducing liver fat content: In HIV patients, the incidence of non-alcoholic fatty liver disease (NAFLD) is high and closely associated with abnormal fat metabolism. Tesamoreli has a positive therapeutic effect on HIV-related NAFLD. In a randomized, double-blind, multicenter study, HIV-infected patients with a hepatic fat fraction (HFF) ≥5% were randomly assigned to the tesamorelin group or the placebo group and treated for 12 months. The results showed that patients in the Tesamoreli group had a more significant reduction in HFF, with an absolute effect size of -4.1% (95% CI -7.6 to -0.7, P = 0.018) and a relative reduction of 37% from baseline (95% CI -67 to -7, P = 0.016). After 12 months of treatment, 35% of patients in the Tesamoreli group had HFF levels below 5%, compared to only 4% in the placebo group (P = 0.0069). This indicates that Tesamoreli effectively reduces liver fat content and improves liver fat metabolism in HIV patients.
Potential effects on liver histology: Analysis of liver gene expression profiles in HIV-NAFLD patients revealed that Tesamoreli downregulated gene sets associated with inflammation, tissue repair, and cell division in the liver. Further proteomics studies showed that Tesamoreli led to a significant reduction in plasma protein levels of vascular endothelial growth factor A (VEGFA), transforming growth factor β1 (TGFB1), and macrophage colony-stimulating factor 1 (CSF1), which are closely associated with liver fibrosis and inflammation. In patients treated with Tesamoreli, the reduction in plasma VEGFA and CSF1 was associated with a decrease in NAFLD activity scores, while the reduction in TGFB1 and CSF1 was associated with a decrease in gene-level fibrosis scores. This suggests that Tesamoreli may exert beneficial effects on liver histology by regulating inflammation and fibrosis-related pathways in the liver.
Figure 3 Relationship of Changes in Plasma TGFB1 and CSF1 with Change in Gene-Level Fibrosis Score in Tesamoreli-Treated Participants.
Regulation of Whole-Body Fat Distribution and Body Composition
Reducing trunk fat: In addition to reducing VAT, Tesamoreli also has a significant regulatory effect on trunk fat in HIV patients. In clinical studies, patients treated with Tesamoreli showed a gradual reduction in trunk fat content, which helps improve body shape and reduce issues such as abdominal protrusion caused by abnormal fat distribution. The reduction in trunk fat is interrelated with the reduction in VAT, collectively improving body composition.
Improving waist circumference: Waist circumference is an important indicator of abdominal fat accumulation. Tesamoreli treatment significantly improves waist circumference in HIV patients. In relevant clinical trials, both Tesamoreli responders with and without back-neck fat showed a significant reduction in waist circumference after 26 weeks of treatment. The improvement in waist circumference not only reflects reduced abdominal fat but is also closely associated with reduced metabolic risks such as cardiovascular disease.
Effects on other body composition parameters: Tesamoreli also has a regulatory effect on other body composition parameters in HIV patients. For example, in some studies, while body mass index (BMI) showed no significant changes, body fat composition improved. Tesamoreli can optimize body fat distribution without affecting overall weight, reduce excessive fat accumulation, increase lean body mass components such as muscle, and enhance patients' body quality.
Application of Tesamoreli in Fat Metabolism in HIV Patients
Target Population
HIV patients with abnormal fat metabolism: Tesamoreli is primarily indicated for HIV patients with abnormal fat metabolism, particularly those with excessive visceral fat (e.g., as determined by abdominal CT or MRI scans showing visceral adipose tissue [VAT] exceeding normal ranges). These patients typically exhibit abdominal obesity, increased waist circumference, and may also present with other manifestations of metabolic syndrome, such as insulin resistance and dyslipidemia.
Conclusion
As an effective therapeutic agent for abnormal fat metabolism in HIV patients, Tesamoreli regulates fat metabolism through multiple mechanisms, playing a significant role in reducing VAT, improving hepatic fat metabolism, regulating whole-body fat distribution, and optimizing body composition.
Sources
[1] Rahman F, de Chantal M, Mesquita P, et al. 935. Effect of Tesamoreli in People with HIV with and without Dorsocervical Fat: Post Hoc Analysis of Phase III Double Blind Placebo Control Trial[J]. Open Forum Infectious Diseases, 2020,7(Supplement_1):S500-S501.DOI:10.1093/ofid/ofaa439.1121.
[2] Clinical Review Report: Tesamoreli (Egrifta)[M]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health, 2016.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=30920787&query_hl=1.
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