@article{milhem_hamilton_skates_wilson_johanningsmeier_komarnytsky_2024, title={Biomarkers of Metabolic Adaptation to High Dietary Fats in a Mouse Model of Obesity Resistance}, volume={14}, ISSN={["2218-1989"]}, url={https://doi.org/10.3390/metabo14010069}, DOI={10.3390/metabo14010069}, abstractNote={Obesity-resistant (non-responder, NR) phenotypes that exhibit reduced susceptibility to developing obesity despite being exposed to high dietary fat are crucial in exploring the metabolic responses that protect against obesity. Although several efforts have been made to study them in mice and humans, the individual protective mechanisms are poorly understood. In this exploratory study, we used a polygenic C57BL/6J mouse model of diet-induced obesity to show that NR mice developed healthier fat/lean body mass ratios (0.43 ± 0.05) versus the obesity-prone (super-responder, SR) phenotypes (0.69 ± 0.07, p < 0.0001) by upregulating gene expression networks that promote the accumulation of type 2a, fast-twitch, oxidative muscle tissues. This was achieved in part by a metabolic adaptation in the form of blood glucose sparing, thus aggravating glucose tolerance. Resistance to obesity in NR mice was associated with 4.9-fold upregulated mitoferrin 1 (Slc25a37), an essential mitochondrial iron importer. SR mice also showed fecal volatile metabolite signatures of enhanced short-chain fatty acid metabolism, including increases in detrimental methyl formate and ethyl propionate, and these effects were reversed in NR mice. Continued research into obesity-resistant phenotypes can offer valuable insights into the underlying mechanisms of obesity and metabolic health, potentially leading to more personalized and effective approaches for managing weight and related health issues.}, number={1}, journal={METABOLITES}, author={Milhem, Fadia and Hamilton, Leah M. and Skates, Emily and Wilson, Mickey and Johanningsmeier, Suzanne D. and Komarnytsky, Slavko}, year={2024}, month={Jan} }
 @article{milhem_skates_wilson_komarnytsky_2024, title={Obesity-Resistant Mice on a High-Fat Diet Display a Distinct Phenotype Linked to Enhanced Lipid Metabolism}, volume={16}, ISSN={["2072-6643"]}, url={https://doi.org/10.3390/nu16010171}, DOI={10.3390/nu16010171}, abstractNote={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, C57BL/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.}, number={1}, journal={NUTRIENTS}, author={Milhem, Fadia and Skates, Emily and Wilson, Mickey and Komarnytsky, Slavko}, year={2024}, month={Jan} }
 @misc{milhem_komarnytsky_2023, title={Progression to Obesity: Variations in Patterns of Metabolic Fluxes, Fat Accumulation, and Gastrointestinal Responses}, volume={13}, ISSN={["2218-1989"]}, url={https://doi.org/10.3390/metabo13091016}, DOI={10.3390/metabo13091016}, abstractNote={Obesity is a multifactorial disorder that is remarkably heterogeneous. It presents itself in a variety of phenotypes that can be metabolically unhealthy or healthy, associate with no or multiple metabolic risk factors, gain extreme body weight (super-responders), as well as resist obesity despite the obesogenic environment (non-responders). Progression to obesity is ultimately linked to the overall net energy balance and activity of different metabolic fluxes. This is particularly evident from variations in fatty acids oxidation, metabolic fluxes through the pyruvate-phosphoenolpyruvate-oxaloacetate node, and extracellular accumulation of Krebs cycle metabolites, such as citrate. Patterns of fat accumulation with a focus on visceral and ectopic adipose tissue, microbiome composition, and the immune status of the gastrointestinal tract have emerged as the most promising targets that allow personalization of obesity and warrant further investigations into the critical issue of a wider and long-term weight control. Advances in understanding the biochemistry mechanisms underlying the heterogenous obesity phenotypes are critical to the development of targeted strategies to maintain healthy weight.}, number={9}, journal={METABOLITES}, author={Milhem, Fadia and Komarnytsky, Slavko}, year={2023}, month={Sep} }