Background: Predominance of adiposity and diabetes is dramatically expanding. Asprosin, a novel adipokine, serve as cross-organ messenger, linking adipose tissue with skeletal muscle. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump mediates Ca2+ entry from sarcoplasm back to its lumen. Sarcolipin (SLN) is an uncoupler of SERCA pump, playing an important role in muscle-based thermogenesis. Aim: We aimed to explore the role of exercise (EX) and/or liposomal curcumin (LP-CUR) to counteract asprosin in the pathogenesis of adiposity by modulating the SLN/SERCA proteins. Materials and method: This study was conducted for 8 weeks through 5 Groups of rats. The control group fed normal diet. While, the others were fed high-fat diet (HFD) either alone HFD group, or with performing EX by running on treadmill at 20 m/min for 1 hour/day, 4 days/week, or received LP-CUR 10 mg/kg/day, or combination of both. Results: The HFD group exhibited significant dyslipidemia, hyperglycemia, insulin resistance, oxidative and sarcoplasmic reticulum stress, rise in body weight gain %, fat pad mass, and decline in lean body mass with reduced physical endurance versus the control group. The asprosin at both mRNA and protein levels were predominantly overexpressed in the HFD group. Fortunately, EX training and/or LP-CUR administration prevented such HFD bad consequences. They caused overexpression of soleus SLN and SERCA proteins, mitochondrial biogenesis, and increased enzymes activities responsible for oxidative metabolism. The core temperature and time to exhaustion were also increased. Conclusion: Our study suggests EX and/or LP-CUR enhanced thermogenesis as an effective strategy to counteract obesity and related comorbidities.