Activation of transsulfuration pathway to maintain cysteine is a thermogenic checkpoint for the conservation of energy.

Pro-longevity dietary interventions such as caloric restriction (CR)1 and methionine restriction2 (MR) are associated with 'browning' of white adipose tissue in rodents, an adaptive response that increases heat production to maintain core-body temperature for the survival of homeotherms3,4. Here, the analysis of metabolome and transcriptome of adipose tissue of healthy humans5 identified that sustained caloric restriction (CR) decreases methionine cycle and lowers cysteine levels despite elevated expression of enzyme cystathionine γ-lyase (CTH), which catalyzes the synthesis of cysteine in the transsulfuration (TSP) pathway6,7. Cysteine starvation of global, but not adipocyte- or hepatocyte-specific Cth deficient mice, triggered lethal thermogenesis through conversion of white adipose tissue into uncoupled "brown"-like adipocytes. This manifests as depletion of energy reserves and drastic weight-loss. Mechanistically, cysteine starvation-induced thermogenesis and energy expenditure increases adipose noradrenaline bioavailability and induces a UCP1-independent response that partially requires FGF21. Therapeutically, reduction of cysteine reversed obesity by increasing thermogenesis and lowering inflammation. These findings establish that adaptation to dietary restriction requires activation of TSP to defend organismal cysteine levels that serves as a thermogenic checkpoint for regulation of core-body temperature and conservation of energy.