Catalase overexpression modulates metabolic parameters in a new ‘stress-less’ leptin-deficient mouse model

Abstract

Oxidative stress plays a key role in obesity by modifying the function of important biological molecules, thus altering obesogenic pathways such as glucose and lipid signaling. Catalase, is an important endogenous antioxidant enzyme that catabolizes hydrogen peroxide produced by the dismutation of superoxide. Recent studies have shown knockdown of catalase exacerbates insulin resistance and leads to obesity. We hypothesized that overexpressing catalase in an obese mouse will modulate obesogenic pathways and protect against obesity. Therefore, we bred catalase transgenic ([Tg(CAT)+/−] mice with Ob/Ob mice to generate the hybrid “Bob-Cat” mice. This newly generated “stress-less” mouse model had decreased oxidative stress (oxidized carbonylated proteins). ECHO-MRI showed lower fat mass but higher lean mass in “Bob-Cat” mice. Comprehensive Lab Animal Monitoring System (CLAMS) showed light and dark cycle increase in energy expenditure in Bob-Cat mice compared to wild type controls. Circulating levels of leptin and resistin showed no change. Catalase mRNA expression was increased in key metabolic tissues (adipose, liver, intestinal mucosa, and brain) of the Bob-Cat mouse. Catalase activity, mRNA and protein expression was increased in adipose tissue. Expression of the major adipokines leptin and adiponectin was increased while pro-inflammatory genes, MCP-1/JE and IL-1β were lowered. Interestingly, sexual dimorphism was seen in body composition, energy expenditure, and metabolic parameters in the Bob-Cat mice. Overall, the characteristics of the newly generated “Bob-Cat” mice make it an ideal model for studying the effect of redox modulators (diet/exercise) in obesity.

Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model

“…We hence generated the "Bob-Cat" stress-less mice model, a hybrid between catalase transgenic mice [Tg(CAT) ± ] [42] and leptin-deficient, obese mice (heterozygous JAX 000632, B6.Cg-Lep ob /J). We have earlier shown that this novel mouse model had lower redox stress and improved adipose function compared to the Ob/Ob phenotype (JAX 000632, B6.Cg-Lep ob /J) and expressed both human and mouse catalase [43].…”

“…We hypothesized that modulating redox stress by altering endogenous antioxidant content (overexpression of catalase) and/or via dietary intervention will improve energy metabolism, adipose tissue function, and overall glucose and lipid homeostasis. To better understand the interplay between redox regulation and dietary intervention in improving energy balance and maintaining insulin sensitivity, we compared the redox effects of a high-fat lard diet (HFD) and a high-fat omega 3-enriched diet (OM3) in a catalase-overexpressing 'stress-less' mice model [43]. In this model, we previously showed the ubiquitous overexpression of catalase altered anthropometric parameters, overall energy metabolism, as well as adipose tissue function in both male and female mice compared to WT controls [43].…”

“…To better understand the interplay between redox regulation and dietary intervention in improving energy balance and maintaining insulin sensitivity, we compared the redox effects of a high-fat lard diet (HFD) and a high-fat omega 3-enriched diet (OM3) in a catalase-overexpressing 'stress-less' mice model [43]. In this model, we previously showed the ubiquitous overexpression of catalase altered anthropometric parameters, overall energy metabolism, as well as adipose tissue function in both male and female mice compared to WT controls [43]. These characteristics make this mice model an excellent method for studying dietary effects of high fat lard and fish oil diets on metabolic homeostasis of both male and females, now critical for all clinical trials.…”

Leptin and Leptin Resistance in the Pathogenesis of Obstructive Sleep Apnea: A Possible Link to Oxidative Stress and Cardiovascular Complications

“…However, it was also shown that leptin replacement therapy significantly downregulated expression of NADPH oxidase in adipose tissue of leptin-deficient ob/ob mice [ 96 ], indicating a protective role of leptin at homeostatic levels. Moreover, leptin production was increased by overexpression of endogenous antioxidant enzyme, catalase that catabolizes hydrogen peroxide produced by the dismutation of superoxide, and it was correlated with improved energy expenditure and decreased inflammatory and oxidative stress markers in ob/ob mice [ 97 ]. The relationship between leptin and oxidative stress has been recently investigated in a mouse model of oxidative stress, demonstrating that increased Nrf2 signaling suppressed oxidative stress and improved leptin resistance in the hypothalamus [ 98 ].…”

3-Amino-1,2,4-Triazole Induces Quick and Strong Fat Loss in Mice with High Fat-Induced Metabolic Syndrome

“…The role of catalase in adiposity is still controversial. On the one hand, catalase overexpression in fat inhibits adiposity [29]. On the other hand, knockout animals for catalase show different metabolic profiles according to the literature.…”