Major causes of morbidity include obesity and associated comorbidities, such as cardiovascular disease and type 2 diabetes. As such, a significant body of research exists and is ongoing in the field of obesity and obesity-related conditions.
Obesity is a complex, multicomponent metabolic disease of energy homeostasis involving central and peripheral mechanisms. Physiological counterregulatory mechanisms are needed to limit weight reduction and hinder weight maintenance.
Targeting the pathways of endogenous nutrient-stimulated hormones has been explored to potentially produce higher efficacy in research models of obesity, via long-acting glucagon-like peptide-1 (GLP-1) receptor agonists. Another nutrient-stimulated hormone, glucose-dependent insulinotropic polypeptide (GIP), is considered to control energy equilibrium through cell-surface receptor signaling in brain and fatty tissue. Theoretically, a chemical that activates the GIP and GLP receptors may be more effective.
Tirzepatide Peptide and Hunger
Studies suggest that Tirzepatide peptide may potentially retard gastric emptying, although this potential appears to wane when tachyphylaxis sets in [i]. The action of Tirzepatide is theorized to be almost entirely regulated by its GLP-1 action, and not at all by GIP activity since its proposed effects are comparable to those found with pure GLP-1R agonists.
Tirzepatide’s alleged effects on stomach emptying have been reported in research studies to possibly be sustained by introducing gradual concentrations in animal test models. Increased satiety, decreased appetite, and cravings are also linked to delayed stomach emptying, creating further avenues for research.
Tirzepatide Peptide and Weight
Researchers suggest that Tirzepatide may induce significant weight reduction as exhibited in studies using murine models. Scientists speculate that Tirzepatide’s long-term potential in weight maintenance appears to be due to the GIP agonism hypothesized to be caused by the peptide. Tirzepatide is believed to affect adiponectin levels by a mechanism that presumably involves GIP’s direct effect on the insulin sensitivity of adipocytes. Research has posited that Tirzepatide may potentially raise insulin sensitivity by activating GIP receptors in adipose tissue. This, in turn, may increase adiponectin levels while decreasing adipose inflammation. The whole image, however, includes more.
The hypothalamic feeding centers are considered to be regulated by GIP signaling in the central nervous system, resulting in reduced food intake and enhanced glucose management. This, in turn, may cause a reduction in overall body mass . Findings imply that Tirzepatide may affect weight via altering adiponectin signaling in adipose tissue and central nervous system (CNS) signaling, which decreases appetite.
Tirzepatide Peptide and the Heart
Tirzepatide, it has been speculated, exhibits some potential to affect adiponectin concentrations. Increased adiponectin levels have been connected with a reduced risk of atherosclerosis, obesity, and cardiovascular disease, whereas lower levels have been connected to an increased risk of these conditions.
Investigations purport that Tirzepatide may potentially improve lipoprotein biomarkers in research models of type 2 diabetes, possibly reducing triglycerides, apoC-III, and lipoproteins. These results suggest that lower adiposity may lead to a decreased risk of cardiovascular disease. A lower risk of heart disease is considered to be linked with increased quantities of good cholesterol (HDL) and triglycerides, which are reduced when adiponectin levels are raised. However, the peptide hormone reportedly appears to increase the levels of cholesterol efflux and possibly decrease scavenger receptors in macrophages, providing possible protection against atherosclerosis. [ii]
Studies have suggested that GLP-1 may be crucial in controlling cardiovascular risk factors directly and indirectly [iii]. These risk factors include hypertension, dyslipidemia, obesity, inflammation, and endothelial cell dysfunction.
Data suggests that GLP-1 signaling may improve end-organ perfusion and lower blood pressure by relaxing blood vessel walls. The upregulation of eNOS, the enzyme in charge of producing nitric oxide and causing vascular relaxation, seems responsible for this impact. Interestingly, in the context of underlying cardiovascular illness and diabetes, these effects seem to be amplified [iii].
Inflammation is considered to be a factor in the development of atherosclerosis. Scientists have not yet exacted the specific process by which GLP-1 signaling may impact physiological proceses, however, they suggest that it may lower inflammation by dampening NF-kappaB signaling, MMP-9 activity, inflammatory cytokine generation, and inflammatory macrophage activity. Furthermore, the effects of a single presentation of a GLP-1R agonist like Tirzepatide might linger for as long as three months [iii]. The current clinical study of Tirzepatide in research models of heart failure is to assess the compound’s medium-term effects [iv].
[i] Urva, Shweta, et al. “The Novel Dual Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 (GLP-1) Receptor Agonist Tirzepatide Transiently Delays Gastric Emptying Similarly to Selective Long‐Acting GLP-1 Receptor Agonists.” Diabetes, Obesity and Metabolism, vol. 22, no. 10, 13 July 2020, pp. 1886–1891, 10.1111/dom.14110.
[ii] H. Yanai and H. Yoshida, “Beneficial Effects of Adiponectin on Glucose and Lipid Metabolism and Atherosclerotic Progression: Mechanisms and Perspectives,” Int. J. Mol. Sci., vol. 20, no. 5, p. 1190, Mar. 2019, doi: 10.3390/ijms20051190.
[iii] M. Tate, A. Chong, E. Robinson, B. D. Green, and D. J. Grieve, “Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes,” Br. J. Pharmacol., vol. 172, no. 3, pp. 721–736, Feb. 2015, doi: 10.1111/bph.12943.
[iv] UCSD, “UCSD Obesity Trial: A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction and Obesity (SUMMIT).” https://clinicaltrials.ucsd.edu/trial/NCT04847557.