Enhancing Host Defense Against Bacterial Pneumonia in Lipodystrophy: Evaluating the Therapeutic Potential of Leptin and Tirzepatide

Respiratory tract infections are a leading cause of death for lipodystrophy patients. Lipodystrophy syndromes are rare disorders characterized by selective loss of adipose tissue, hyperphagia, severe insulin resistance, type 2 diabetes, hepatic steatosis, and leptin deficiency. The life spans of lipodystrophy patients are reduced by 30 years compared with the general population. While metabolic complications of lipodystrophy are well-documented, the impact on immune function and susceptibility to infections remains poorly understood. Metreleptin, an FDA approved treatment, significantly improves metabolic complications of lipodystrophy but its impact on respiratory tract infections has not been determined. We have shown that leptin deficient mice have impaired host defense against bacterial pneumonia and that exogenous leptin improves pulmonary bacterial clearance and survival. While metreleptin treatment is effective, many patients discontinue treatment due to the development of anti-leptin antibodies. As an alternative, treatment with tirzepatide, a dual acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) agonist, was shown to be effective in a clinical trial to control metabolic complications of lipodystrophy. However, little is known regarding the impact of tirzepatide on the risk of respiratory tract infections in lipodystrophy or diabetic patients. To address the lack of research on lipodystrophy and bacterial pneumonia, we infected adipocyte-specific lamin A/C knockout (Lmna ADKO) mice, a model of lipodystrophy, and wild type (WT) mice with an intrapulmonary dose of Klebsiella pneumoniae (K.pneumoniae) a common cause of pneumonia in diabetic patients. Lmna ADKO mice exhibited higher lung bacterial burdens as compared with their WT counterparts. In addition, alveolar macrophage phagocytosis of K. pneumoniae and reactive oxygen intermediate production were reduced in cells from Lmna ADKO mice. The long-term goal of this research is to understand how metabolic disease impairs host defense against respiratory tract infections. The overall objective of the proposed research is to determine if leptin, tirzepatide, or a combination of these drugs improve host defense in Lmna ADKO mice following infection with K. pneumoniae. The results of these studies will determine if correcting glucose homeostasis and leptin deficiency with leptin or correcting glucose homeostasis alone with tirzepatide improves host defense. Results from our studies will inform clinicians regarding the best course of treatment for lipodystrophy to normalize glucose homeostasis and mitigate the risk of respiratory tract infections. The central hypothesis is that lipodystrophy impairs host defense against Klebsiella pneumonia by impairing alveolar macrophage phagocytosis and bacterial killing due to metabolic disturbances and leptin deficiency. Correcting these defects by administering leptin will be more effective than tirzepatide and combining leptin and tirzepatide will result in the most effective improvements in host defense against Klebsiella pneumonia. Project Number: 1R21AI196410-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: PETER MANCUSO | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $429,000 | Activity Code: R21 | Study Section: Lung Immunology and Infection Study Section[LII] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19641001