Cysteine deficiency triggers adipose tissue thermogenesis and weight-loss

Caloric restriction (CR) and methionine restriction driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue (WAT), a metabolic response that increases heat production to defend core-body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight-loss induced by CR in humans reduces thiol-containing sulfur amino acid cysteine in WAT. Systemic cysteine-depletion in mice causes lethal weight-loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine restriction induced adipose browning and weight-loss requires sympathetic nervous system derived noradrenaline signaling via ß3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight-loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss. Overall design: RNA-seq profiling of brown (BAT), visceral (EFAT) and subcutaneous (SFAT)adipose depots of Cth+/+ and Cth-/- mice fed with control or cystine deficient diet.