We hypothesized that modulating redox stress by altering end

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]. 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. Our study showed that OM3 enriched diet, in Vincristine sulfate to the HFD intervention activated the GPR120-Nrf2 cross-talk to maintain balanced energy metabolism, normal circadian rhythm and insulin sensitivity in mice overexpressing catalase compared to the WT controls. Therefore, increasing endogenous antioxidant production in combination with an OM3 rich diet will maintain energy balance, improve adipose tissue function, and lower risk of obesity and its comorbidities.
Methods
Results
Discussion Obesity and its comorbidities are characterized with increased levels of ROS that alter lipid and glucose homeostasis in key metabolic organs [3,66,67]. This leads to increased body weight and fat mass thus increasing risk for hyperglycemia, hyperlipidemia, hyperleptinemia, systemic inflammation, and IR [3]. Both endogenous and exogenous antioxidant supplementation, known to mitigate the negative effects of redox stress, were shown to lower the levels of ROS in these metabolic diseases [40,[68], [69], [70]]. Additionally, in both lean and obese rodent models, dietary interventions, such as those rich in OM3 fatty acids (including EPA and DHA) in contrast to saturated fatty acids (lard diet), also lowered body weight and fat mass, increased insulin sensitivity, and induced browning of white adipose tissue through anti-inflammatory actions [18,23,26,71]. However, the mechanisms leading to these beneficial effects were not clearly defined. We recently showed that mice overexpressing catalase in a genetically obese background (Bob-Cat), in contrast to its wild-type littermates, significantly lowered redox stress (‘stress-less’ mice), improved energy metabolism, and altered the expression of key adipocytokines [43]. The overexpression of catalase in this mouse model with a genetic obese background was implicated to be the key factor responsible for these effects. Therefore, these mice presented characteristics of an effective model to study the interaction between redox regulation and dietary intervention, on adipose tissue function and glucose and lipid signaling in a “diet-induced obesity” model. In the present study, eight weeks (chronic effect) of dietary intervention in the ‘stress-less’ mice model overexpressing catalase, in comparison to their WT controls, showed that the high-fat omega-3 enriched (OM3) diet, in contrast to the high-fat lard (HFD) diet, stabilized body weight and fat mass, maintained balanced energy metabolism and normal circadian rhythm, and sustained insulin sensitivity by regulating GPR120-Nrf2 cross-talk. Administration of OM3 diet, in contrast to the HFD fed animals, for 8 weeks showed that mice overexpressing catalase (male and female Bob-Cats), maintained or lowered body weight and fat mass, similar to that observed in NC fed mice groups, despite a lower food intake (total g and kcal/g consumed) of chow provided ad libitum. Decreased food intake when fed HFD in comparison to a normal rodent diet has been reported in previous studies as the result of a higher caloric and satiating diet [72]. These observations support the importance of the composition of a meal on fat accumulation and distribution during weight management/weight loss therapies in humans [73]. This is of particular interest in obese subjects, where an excessive accumulation of visceral fat mass elevates the risk of numerous health conditions including coronary heart disease, IR, osteoarthritis, and hypertension [74], which further contributes to the 8 year reduction in life expectancy in these individuals [[75], [76], [77]]. In contrast, the increased life expectancy observed in studies conducted in catalase overexpressing mice [78] may be attributed to the type of diet consumed.