A neural metabolic memory of diet restriction influences rebound weight gain

A major hurdle in the battle against obesity is not only the ability to promote weight loss but the inability to maintain a lower body weight indefinitely. This issue is potentially relevant to 1.9 billion overweight and obese people worldwide. Therefore, this proposal focuses on understanding how neural circuits controlling food intake and energy metabolism change in response to weight loss in obese mice. We propose that weight loss creates a metabolic memory of diet restriction to program greater food intake and rebound weight gain in the future, independent from starting body weight. This novel idea is inspired by a 25-year twin study showing that dieters are more prone to future weight gain independent from genetic factors. Moreover, there is strong evidence in humans that persistent dieting, enforced semi-starvation or Army training causes excessive weight regain beyond starting levels and leads to greater fat mass accumulation (weight overshoot) overtime. This project examines a neural mechanism for this metabolic memory of dietary restriction that increases rebound energy intake and weight gain over time. How does the brain sense energy deficit? Within the arcuate nucleus of the hypothalamus reside ~8,000 Agouti-related peptide neurons (Agrp neurons – so called due to lack of expression anywhere else in the brain). These hunger-sensing Agrp neurons, which co-express Neuropeptide Y (NPY) and GABA, increase their firing in response to energy deficit and promote food (energy) intake, nutrient partitioning (i.e. decreased fat utilisation and increased fat storage independent from food intake) and decreased energy expenditure and thermogenesis. These physiological changes are essential to conserve and replenish the body’s energy supply when energy intake is less than energy expenditure. These neurons also communicate with numerous other brain regions to influence motivation, memory, and mood, all of which optimise current and future food-seeking opportunities. The premise of this project is that repeated periods of diet restriction, similar to diet cycling in humans, engage hunger-sensing Agrp neurons outside and beyond the boundaries of their normal daily activity. As a result, Agrp neuronal activity is reprogrammed to create a ‘metabolic memory’ of diet restriction, which maximises future energy intake and storage efficiency (increases adipogenesis [nutrient partitioning] and decreases energy expenditure [thermogenesis]), when the opportunity arises. We believe this could underpin the often observed rebound weight gain in humans, after the cessation of diet restriction. Hypothesis - Agrp neurons program a metabolic memory of diet restriction, which promotes greater than normal weight regain (weight overshoot). Aim 1 – Determine how diet restriction alters Agrp neuronal activity (greater metabolic memory) in obese mice, using calcium imaging ex vivo and in vivo. Aim 2 – Determine whether artificial activation or inhibition of Agrp neurons creates or prevents the formation of a metabolic memory and affects energy homeostasis in obese mice. Aim 3 – Determine whether artificial activation or inhibition of Agrp neurons creates or prevents the formation of a metabolic memory that influences the dopamine brain reward system. Significance - By reassessing rebound weight gain as the manifestation of a metabolic “memory” of the magnitude of weight loss, we aim to refocus potential therapeutic and treatment strategies to curtail obesity and weight regain after weight loss.