Relapse Of Obesity Is Attributed To Immune System Mediated Obesity Memory

Obesity is a medical condition in which excessive body fat is accumulated,resulting in increased incidence of many severe diseases such as cardiovascular diseases,type ? diabetes and some types of cancer.Unfortunately,current therapies of obesity,including lifestyle intervention,calorie intake control,physical activity enhancement,various medication and bariatric surgeries,are often ineffective due to unavoidable body weight regain after treatment interruption and during treatment.Regain of lost body weight will stage a comeback of obesity related diseases.This situation makes weight regain the most urgent and difficult issue to be resolved.We found that weight regain after weight loss was attributed to memory of previous obese status which promotes relapse of obesity.C57BL/6J mice went through diet-induced obesity and calorie restriction-induced weight loss displayed faster weight regain after re-fed ad libitum when comparing with mice who had never experienced obesity,no matter high-calorie or low-calorie food were assigned.Besides,memory of obese status can last at least for two months after weight reduction in mice,demonstrating that obesity memory is a longlasting effect rather than a transient phenomenon.Above results demonstrated that obesity can be memorized in obese individuals for a long time,resulting in more rapid body weight regain in the future despite previous successful weight loss.However,disagree with previous studies of weight regain,our data suggested that obesity memory was not aroused from hyperphagia,reduced thermogenesis or declined metabolic rate.In fact,we found that immune system functions were activated not only after weight regain but also before weight regain when mice had lost extra weight and were exhibiting normal body fat percentage.Intriguingly,immunodeficient Ragl-/-mice and immuno-suppressed C57BL/6J mice failed to develop obesity memory.Obesity memory can be re-estabolished in Ragl-/-mice through introducing splenocytes from C57BL/6J mice that had been subjected to weight gain and weight loss,suggesting necessity of immune system functions for generating obesity memory.We also found that it was able to both transfer obesity memory into untreated naive mice and eliminate existed obesity memory by reconstructing immune system via bone marrow transplantation.Furthermore,we observed significantly upregulated CD4+ T lymphocytes during development of obesity memory,especially pro-inflammatory Th1 and Th17 cells.Depleting CD4+ T lymphocytes in C57BL/6J mice led to suppressed obesity memory.More strikingly,CD4+ T lymphocytes isolated from bone marrow solely can introduce obesity memory into naive normal mice,indicating that CD4+ T lymphocytes played a pivotal role in establishing obesity memory.In summary,our findings revealed that obesity can be memorized by the body,which offers a novel explanation of inevitable weight regain in various treatments of obesity.More importantly,we found that immune system functions,especially CD4+ T lymphocytes,serve as the key character in producing and carrying obesity memory,which provides new insights into obesity-related researches and anti-obesity therapeutics.