Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice

Abd Al-Roof Higazi; Emad Maraga; Saja Baraghithy; Shiran Udi; Shahar Azar; Ann Saada; Benjamin Glaser; Dana Avrahami; Suhair Abdeen; Zenab Hamdan; Joseph Tam; Rami Abu Fanne

doi:10.1016/j.isci.2024.108802

Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice

iScience. 2024 Jan 12;27(2):108802. doi: 10.1016/j.isci.2024.108802. eCollection 2024 Feb 16.

Authors

Abd Al-Roof Higazi¹, Emad Maraga¹, Saja Baraghithy², Shiran Udi², Shahar Azar², Ann Saada^{3

4

5}, Benjamin Glaser⁶, Dana Avrahami⁷, Suhair Abdeen¹, Zenab Hamdan⁶, Joseph Tam², Rami Abu Fanne^{1

8}

Affiliations

¹ Department of Clinical Biochemistry, Hebrew University-Hadassah Medical Center, Jerusalem 9112001, Israel.
² Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
³ Department of Genetics, Hadassah Medical Center, Jerusalem, Isarel.
⁴ Faculty of Medicine, Hebrew University, Jerusalem, Isarel.
⁵ Department of Laboratory Sciences, Hadassah Academic College, Jerusalem, Isarel.
⁶ Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
⁷ Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
⁸ Department of Cardiology, Hillel Yaffe Medical Center, Hadera, Israel.

Abstract

Inflammation is consistently linked to dysmetabolism. In transgenic mice (Def^+/+) model the neutrophilic peptide, alpha defensin, proved atherogenic. This phenotype occurred despite favorable cholesterol and glucose levels, and lower body weight and blood pressure. In this study, integration of metabolic&behavioral phenotyping system, endocrine, biochemical and mitochondrial assessment, pathological and immunohistochemical tests, and multiple challenge tests was established to explore the metabolic impact of alpha defensin. Compared to the control group, Def^+/+ mice exhibited lower total energy expenditure and carbohydrate utilization, and higher fat oxidation. Their ACTH-cortisol and thyroid profiles were intact. Intriguingly, they had low levels of glucagon, with high ammonia, uric acid, triglyceride, and lactate. Mitochondrial evaluations were normal. Overall, defensin-induced hypoglucagonemia is associated with lipolysis, restricted glucose oxidation, and enhanced wasting. Def^+/+ mice may be a useful model for studying the category of lean, apparently metabolically healthy, and atherosclerotic phenotype, with insight into a potential inflammatory-metabolic link.

Keywords: Cell biology; Endocrinology; Molecular physiology.