###### Abstract  
Individually, metabolic variations can significantly influence predisposition to obesity in the form of the obesity-prone (super-responders) and obesity-resistant (non-responders) phenotypes in response to modern calorie-dense diets. In this study, C57 BL/6J mice (n = 76) were randomly assigned to either a low-fat diet (LFD) or a high-fat diet (HFD) for 6 weeks, followed by selection of the normally obese (HFD), non-responders (NR), super-responders (SR), or super-responders switched back to the low-fat diet (SR-LFD) for an additional 8 weeks. SR mice showed the highest gains in body weight, lean and fat body mass, and total and free water, in part due to increased feed efficiency, despite having a respiratory exchange ratio (RER) similar to that of NR mice. A switch to the LFD was sufficient to revert most of the observed physiological changes in the SR-LFD mice; however, voluntary physical activity and exercise capacity did not return to the basal level. NR mice showed the highest food intake, lowest feed efficiency, increased oxygen consumption during the light (rest) cycle, increased physical activity during the dark (active) cycle, and increased heat production during both cycles. These variations were observed in the absence of changes in food intake and fecal parameters; however, NR fecal lipid content was lower, and the NR fecal microbiome profile was characterized by reduced abundance of _Actinobacteria_. Taken together, our findings suggest that NR mice showed an increased ability to metabolize excessive dietary fats in skeletal muscle at the expense of reduced exercise capacity that persisted for the duration of the study. These findings underscore the need for further comprehensive investigations into the mechanisms of obesity resistance, as they hold potential implications for weight-loss strategies in human subjects. dietary fats; energy substrate; body composition; metabolic rate; individual variability; personalized nutrition +
Footnote †: journal: _Nutrients_  
0000-0002-4300-3300-0000]M.M. this and 750 other minor GWAS loci known to date explain only 6% of variation [5]. Recent additional GWAS that focused on more refined obesity outcomes such as resistance to weight gain suggested that the characterization of obesity-resistant (non-responders) phenotypes may provide an alternative understanding of the metabolic complexity of body weight regulation [6]. Dietary fats are essential nutrients and a concentrated source of energy that serves various vital functions in the human body [7]. Consuming fats contributes to feelings of fullness and satisfaction, signaling to the brain that the body has received sufficient energy [8]. Unlike carbohydrates, which are stored in limited quantities as glycogen in the liver and muscles, fats can be stored in adipose tissue in virtually unlimited amounts [1]. While daily carbohydrate balance is tightly regulated so that the majority of carbohydrates are immediately and preferentially metabolized when available [9], dietary fats are primarily targeted for deposition and storage [10]. Insulin secreted in response to the carbohydrate load of a mixed meal further facilitates fat storage and decreases fat oxidation [11]. Previous rodent studies suggested that progressive metabolic abnormalities in response to calorie-dense meals follow the sequence of hyperinsulinemia; increased adipocyte size; greater adiposity; lower energy expenditure; and, eventually, increased hunger [12]. The excess energy is therefore deposited into conventional adipose depots, as well as ectopic non-target tissues like the liver and muscle based on the individual, hypothetical body weight set points, and patterns of fat accumulation [13]. A few previous animal studies were aimed at understanding the differences between the obesity-prone versus obesity-resistant phenotype, with limited success.