Dual GLP-1/GIP agonist, tirzepatide, increases hypercapnic ventilatory response in diet-induced obese mice

Background: Obesity hypoventilation syndrome (OHS), the most severe form of sleep disordered breathing (SDB), affects over 6 million individuals in the US. OHS is manifested by daytime hypercapnia due to a defect in the hypercapnic ventilatory response (HCVR). Glucagon-like peptide receptor-1 (GLPR-1) agonists liraglutide and tirzepatide induce weight loss and treat SDB in obese patients, but it is unknown if their therapeutic effect on SDB is entirely due to weight loss or there is an independent effect on control of breathing. Objective: To examine the effect of the dual GLP-1/GIP agonist, tirzepatide, on baseline breathing and the HCVR in C57BL/6J male mice with diet induced obesity (DIO) and determine if this effect is independent of metabolism. Methods: C57BL6 male mice with DIO (n=8) were treated in acute (a single dose of 10 nmol/kg tirzepatide subcutaneously, SC) and chronic treatment (10nmol/kg once a day for 7 days) crossover experimental protocols in a random order. Mice were allowed a two-week washout period before the crossover experiments. Minute ventilation (VE) was measured during quiet wakefulness at normocapnia and 8% CO 2 in a thermoneutral environment (28-30°C) after each treatment. HCVR was calculated as the slope of VE versus inspired CO 2 using linear least-squares regression. Metabolic studies (oxygen consumption, VO 2 , and CO 2 production, VCO 2 ) were performed on Day 1 and Day 7 in the thermoneutral environment following the same acute and chronic protocols using the SABLE Systems unit. Results: After a single dose of tirzepatide, normocapnic ventilation did not change, whereas VE at hypercapnic conditions increased due to increases in tidal volume (VT) from 0.46 (mL/breath) to 0.52 (mL/breath) (p= 0.0003). There was a significant reduction of VCO 2 without a change in VO 2 resulting in a decrease in the respiratory exchange ratio (RER, 0.82 to 0.75) indicating a switch to utilization of fat. After 7 days of treatment, tirzepatide increased normocapnic and hypercapnic VE and the HCVR. Hypercapnic VE increased dramatically from 3.58 (mL/min/g) to 5.71 (mL/min/g) (p= 0.0038), and the HCVR increased from 0.34 (Δml/min/Δ%CO 2 /g) to 0.52 (Δml/min/Δ%CO 2 /g) (p= 0.0391). However, changes in VE after 7 days of treatment occurred in the settings of dramatic weight loss and hypermetabolism with VCO 2 increasing from (light phase: 1194 to 1771 mL/kg/h; dark phase: 1488 to 1862 mL/kg/h) and VO 2 increasing from (light phase: 1464 to 2427 mL/kg/h; dark phase: 1807 to 2568 mL/kg/h). RER continued to be decreased due to fat oxidation (light phase: 0.8102 to 0.7283; dark phase: 0.8182 to 0.7233). Conclusions: Acute and chronic tirzepatide treatment switched metabolism to burning fat and increased hypercapnic sensitivity. An increase in hypercapnic ventilation after a single dose of tirzepatide (acute protocol) was independent of metabolism, since VCO 2 was decreased. Chronic tirzepatide treatment greatly increased baseline and hypercapnic VE and HCVR in the settings of weight loss and hypermetabolism with increased utilization of fat. We were unable to determine if the respiratory effects of 7-day tirzepatide treatment were independent of metabolism. Grant support: R01HL128970, R01HL174409 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.