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 β3-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. 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.