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Retatrutide-
GLP-1R agonists are thought to primarily mediate weight loss by reducing food intake [49,53]. There is observational data to infer an additive and possibly synergistic effect of exercise with GLP-1R agonism on weight loss, suggesting non-anorectic mechanisms that are not well characterized [5,66]. The contribution of GcgR agonism to weight loss appears to be primarily mediated by an increase in energy expenditure as suggested by our data; it is hypothesized that hepatic glucose mobilization for consumption in peripheral tissues, including the fat, is primarily responsible.
The data presented here demonstrate that the potency of GcgR agonism defines the maximal weigh-lowering capacity of the triple agonist, presumably through multiple mechanisms of increased energy expenditure, insofar as increasing in vitro GcgR potency with respect to cAMP production prognosticates in vivo weight reduction
Critically, our data suggest that the differentiating factor for this superior weight loss effect is achieved through an increase in energy expenditure, given the elevated energy expenditure in combination with similar reductions in food intake between maximally effective triple agonist and tirzepatide (and other co-agonist) groups
Glucagon is broadly thought to have cardio-stimulatory effects via GcgR expressed on the myocardium [58]. GcgR mono-agonists are known to increase heart rate and contractility, which has led to the suggestion for them to be used as a treatment for low cardiovascular output in acute settings. However, human efficacy data for this strategy is scant.
Dose-dependent increases in heart rate and decreases in systolic blood pressure were observed, which returned to near BL by Day 29.
Dose-dependent increase in heart rate and incidents of mild to moderate cardiac arrythmias raise cardiovascular safety concerns and signify that carrying out long-term cardiovascular outcome trials (CVOTs) will be critical.
Glucagon enhances metabolic rates by stimulating oxygen consumption in brown adipose tissue (BAT), as revealed by increased BAT temperature in rats (61, 62). Glucagon also exerts lipolytic effects on the white adipose tissue by inhibiting lipogenesis and stimulating lipolysis (34). The lipolytic effect is mediated by the activation of the hormone-sensitive lipase (HSL) in the adipocytes (63) and it is amplified by indirect mechanisms including the secretion of growth hormone (64), cortisol (65), and epinephrine (66).
Indeed, glucagon stimulates the formation of ketone bodies by constantly supplying nonesterified fatty acid to the liver (68, 69) and blocking the hepatic glycolytic pathway (70). These result in enhanced fatty acid oxidation in the mitochondria and potentiation of hepatic ketogenesis (34, 70)
Avik Ray (2023) Retatrutide: a triple incretin receptor agonist for obesity management, Expert Opinion on Investigational Drugs, 32:11, 1003-1008, DOI: 10.1080/13543784.2023.2276754
Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, Kruse Hansen AM, Olsen AK, Perez-Tilve D, DiMarchi RD, Finan B. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab. 2022 Sep;63:101533. doi: 10.1016/j.molmet.2022.101533. Epub 2022 Jul 7. PMID: 35809773; PMCID:
Franco Folli, Finzi, G., Manfrini, R., Galli, A., Casiraghi, F., Centofanti, L., Berra, C., Fiorina, P., Davalli, A. M., Stefano La Rosa, Perego, C., & Higgins, P. (2023). Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. American Journal of Physiology-Endocrinology and Metabolism, 325(5), E595–E609. https://doi.org/10.1152/ajpendo.00236.2023
GLP-1R agonists are thought to primarily mediate weight loss by reducing food intake [49,53]. There is observational data to infer an additive and possibly synergistic effect of exercise with GLP-1R agonism on weight loss, suggesting non-anorectic mechanisms that are not well characterized [5,66]. The contribution of GcgR agonism to weight loss appears to be primarily mediated by an increase in energy expenditure as suggested by our data; it is hypothesized that hepatic glucose mobilization for consumption in peripheral tissues, including the fat, is primarily responsible.
The data presented here demonstrate that the potency of GcgR agonism defines the maximal weigh-lowering capacity of the triple agonist, presumably through multiple mechanisms of increased energy expenditure, insofar as increasing in vitro GcgR potency with respect to cAMP production prognosticates in vivo weight reduction
Critically, our data suggest that the differentiating factor for this superior weight loss effect is achieved through an increase in energy expenditure, given the elevated energy expenditure in combination with similar reductions in food intake between maximally effective triple agonist and tirzepatide (and other co-agonist) groups
Glucagon is broadly thought to have cardio-stimulatory effects via GcgR expressed on the myocardium [58]. GcgR mono-agonists are known to increase heart rate and contractility, which has led to the suggestion for them to be used as a treatment for low cardiovascular output in acute settings. However, human efficacy data for this strategy is scant.
Dose-dependent increases in heart rate and decreases in systolic blood pressure were observed, which returned to near BL by Day 29.
Dose-dependent increase in heart rate and incidents of mild to moderate cardiac arrythmias raise cardiovascular safety concerns and signify that carrying out long-term cardiovascular outcome trials (CVOTs) will be critical.
Glucagon enhances metabolic rates by stimulating oxygen consumption in brown adipose tissue (BAT), as revealed by increased BAT temperature in rats (61, 62). Glucagon also exerts lipolytic effects on the white adipose tissue by inhibiting lipogenesis and stimulating lipolysis (34). The lipolytic effect is mediated by the activation of the hormone-sensitive lipase (HSL) in the adipocytes (63) and it is amplified by indirect mechanisms including the secretion of growth hormone (64), cortisol (65), and epinephrine (66).
Indeed, glucagon stimulates the formation of ketone bodies by constantly supplying nonesterified fatty acid to the liver (68, 69) and blocking the hepatic glycolytic pathway (70). These result in enhanced fatty acid oxidation in the mitochondria and potentiation of hepatic ketogenesis (34, 70)
Avik Ray (2023) Retatrutide: a triple incretin receptor agonist for obesity management, Expert Opinion on Investigational Drugs, 32:11, 1003-1008, DOI: 10.1080/13543784.2023.2276754
Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, Kruse Hansen AM, Olsen AK, Perez-Tilve D, DiMarchi RD, Finan B. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab. 2022 Sep;63:101533. doi: 10.1016/j.molmet.2022.101533. Epub 2022 Jul 7. PMID: 35809773; PMCID:
Franco Folli, Finzi, G., Manfrini, R., Galli, A., Casiraghi, F., Centofanti, L., Berra, C., Fiorina, P., Davalli, A. M., Stefano La Rosa, Perego, C., & Higgins, P. (2023). Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. American Journal of Physiology-Endocrinology and Metabolism, 325(5), E595–E609. https://doi.org/10.1152/ajpendo.00236.2023
