Author
HERNANDEZ-CARRETERO, ANGELINA - University Of San Diego | |
WEBER, NATALIE - University Of San Diego | |
LA FRANO, MICHAEL - California Polytechnic State University | |
YING, MEI - University Of San Diego | |
LANTERO RODRIGUEZ, JUAN - California Polytechnic State University | |
SEARS, DOROTHY - University Of San Diego | |
WALLENIUS, VILLE - University Of Gothenburg | |
BORGESON, EMMA - University Of Gothenburg | |
Newman, John | |
OSBORN, OLIVIA - University Of San Diego |
Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 8/16/2017 Publication Date: 11/1/2017 Citation: Hernandez-Carretero, A., Weber, N., La Frano, M.R., Ying, M., Lantero Rodriguez, J., Sears, D.D., Wallenius, V., Borgeson, E., Newman, J.W., Osborn, O. 2017. Obesity-induced changes in lipid mediators persist after weight loss. International Journal of Obesity. 46:11-21. https://doi.org/10.1016/j.nutres.2017.07.006. DOI: https://doi.org/10.1016/j.nutres.2017.07.006 Interpretive Summary: Obesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated. Subjects/Methods: We fed C57BL6 mice a high fat diet to generate obesity and then switched the diet to a lower fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues including adipose, liver, muscle, hypothalamus and plasma. Results: We found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore, the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss. Conclusions: These results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight. Technical Abstract: Obesity induces significant metabolic changes including shifts in the production of molecules in the body that are responsible for the regulation of inflammation, vascular function, and energy intake and utilization. However, the extent to which these obesity-induced changes in these physiological mediator persist after weight loss has not been investigated. To investigate this question, we fed mice a high fat diet to generate obesity and then switched the diet to a lower fat diet to induce weight loss. We performed an expansive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues including adipose, liver, muscle, hypothalamus and plasma. We found that changes induced by obesity were largely reversible in most metabolic tissues, but adipose tissue retained a persistent obese metabolic signature. In particular, prostaglandin signaling was perturbed in the obese state and lasting increases in prostaglandin D2 (PGD2) and its downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore, the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. In mice, inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. To determine if these observations in mice t4anslated to the human condition, adipose biopsies from lean and obese individuals were analyzed. As in the mice, increased HPGDS expression was observed in human adipose tissues from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss. Together, these results suggest that lasting changes in the prostaglandin D metabolism induced by obesity persist after weight loss. As these factors are known to regulate of appetite, body temperature, hormone release, odor and pain responses, and the sleep-wake cycle, perturbation of this system may play a role in the biological drive to regain weight. |