Modulation of Hypothalamic Activity Alters Appetite in a Novel Antioxidant Mouse
Authors: Amos Deborah Lynn , Efaw Logan , Cook Carla , Massie Melissa , Mitchell Noah , Gudivada Akhil , Santanam Nalini 
Published: November 2023

BackgroundObesity is a global health threat. Oxidative stress is a consequence of poor nutrition which plays a key role in obesity and other metabolic diseases. Appetite is tightly regulated by orexigenic and anorexigenic pathways within the hypothalamus. It is implicated that oxygen‐derived free radicals alter the function of metabolic tissues leading to altered glucose and lipid homeostasis. Catalase is an antioxidant enzyme that helps to catabolize hydrogen peroxide generated by superoxide dismutation and thus reducing oxidative stress.HypothesisWe hypothesized that excess catalase expression will deter oxidative stress mediated appetite dysregulation by preventing improper signaling within the hypothalamus.MethodsWe tested our hypothesis in studying appetite regulation and obesogenic changes in Catalase transgenic (Cat‐tg) mice (n=4) that expressed 3–4 fold excess catalase as well as the newly engineered Bob‐Cat mice (n=4), which is a hybrid of Cat‐tg and the leptin resistant obese Ob‐Ob mice (study approved by MU IACUC). Body fat composition using ECHO‐MRI and metabolic changes using CLAMS (Comprehensive Laboratory Animal Monitoring System) were measured. Ob‐Ob mice and C57Bl6 mice were used as controls for lean and obese phenotypes. Changes in appetite regulating genes (POMC‐Proopiomelanocortin and Npy‐Neuropeptide Y) were determined in the hypothalamus obtained from all groups of mice. Adipokines, catalase enzyme activity, and oxidative stress levels were measured in the adipose tissue of all mice. ANOVA was used for statistical comparisons using GraphPad PRISM or SPSS.ResultsThough there was an increased leptin expression in the adipose tissue of Bob‐Cat mice compared to Cat‐tg (>100 fold) mice, there was a lowering of fat to lean ratio in both these mice genotypes compared to the Ob‐Ob mice. CLAMS showed no differences in RER or food intake between the groups however heat production was higher in Cat‐tg and Bob‐cat mice compared to C57Bl6. Cat‐tg mice showed an induction in the anorexigenic POMC (>2.5 fold) and a decrease in orexigenic Npy (<0.5 fold) levels. In contrast, the Bob‐Cat mice showed a reduction in both these appetite genes in comparison to the C57Bl6 mice. Adiponectin, monocyte chemotactic protein‐1 (MCP‐1) and other adipokines were differentially modulated in the two groups of mice.ConclusionIt is evident through ECHO‐MRI, CLAMS, and gene expression data that the over expression of catalase in the Bob‐Cat mice has modulated hypothalamic appetite regulation and the fat to lean mass ratio resulting in lowered obesogenic fat mass. This suggests that excess antioxidant (Catalase) genotype, through regulating metabolic pathways, might lower obesity and thus improve the overall nutritive state. The effect of dietary manipulation (high fat and omega‐3 fat) and exercise is currently being investigated.Support or Funding InformationSupported by NIH Grant 5R01HL‐074239 (NS) and 5P20RR016477 to the West Virginia IDeA Network for Biomedical Research Excellence