Uncovering the neuro-immune mechanisms driving the memory of obesity – MEMOBESE

Background: Obesity currently touches 17% of the adult French population and, by leading to diabetes, cardiovascular disease and certain forms of cancer, it represents an important medical and socio-economic burden. Treating obesity can be successful only if weight loss is maintained over time and weight regain is avoided. Unfortunately, most patients with obesity who receive weight loss interventions eventually exhibit weight regain. Hence, there is an important and urgent need to understand the mechanisms underlying the failure to maintain a lower body weight in the post-obese state.
To continuously adjust energy availability at the organism level, the brain hypothalamus and the adipose tissue must interact through blood-borne and nervous pathways, with the hypothalamic-sympathetic nervous system (SNS) top-down signaling being key in this context. Beyond an obvious role for hypothalamic neurons and adipocytes, recent studies have pointed to the involvement of hypothalamic microglia (the brain resident macrophages) and adipose tissue macrophages in the regulation of energy balance, as these immune cell types critically affect the functions of neurons and adipocytes, respectively, by regulating inflammatory responses among other mechanisms.
Rationale and objectives: Here we hypothesize that after an episode of obesity, an altered neuro-immune crosstalk, involving hypothalamic microglia, the SNS and adipose tissue macrophages, drives a new, higher, body weight set-point by modifying use of energy substrates as well as systemic and tissue inflammatory responses. Our aims are: 1) To characterize the putative mechanisms underlying this altered neuro-immune crosstalk; 2) To establish their causality in modifying the body weight set-point and ensuing weight regain; 3) To determine their translational relevance in patients with weight regain after bariatric surgery.
Methods: To reach these objectives, we will use an experimental mouse model based on diet switch to mimic weight gain/weight loss/weight regain in which behavioral and in vivo metabolic studies will be combined with histological, molecular and biochemical analyses. Some of these studies will be carried out also on adipose tissues samples of bariatric surgery patients with/without weight regain to assess translatability of the findings towards humans. Ad hoc approaches, including generation of transgenic mice, pharmacology and use of RNAseq and cell metabolomics, will then provide in depth information on the roles of hypothalamic microglia, SNS and adipose tissue macrophages in the metabolic changes that accompany the post-obese state and that favor weight regain.
Originality: Our project stems from an original and timely hypothesis proposing that the body acquires a memory of past obesity episodes through changes in the neuroimmune-SNS crosstalk involving the hypothalamus and the adipose tissue, which in turn favor ensuing body weight gain and metabolic alterations. The scientific objectives that we therefore aim at reaching through MEMOBESE are novel and original, while sitting on several published and unpublished observations that overall support the hypothesis proposed and its logic.
Expected results and potential benefits: MEMOBESE is expected to deliver greater understanding of the biological mechanisms at the core of the failure of weight loss maintenance. In the short term, this knowledge is expected to advance the fields of Physiology, Nutrition, Neuroscience, Immunology and Metabolism. In the medium and long term, the evidence provided will foster further studies on identified mechanisms, potentially leading to more effective treatment strategies and to the use of novel biological markers to better characterize and stratify patients for improved medical care.