Leptin Mediates the Effects of Sulfur Amino Acid Restriction on Food Intake and Body Weight in Mice

• SAAR increases food intake which is associated with increased hypothalamic orexigenic mRNA expression despite weight loss in obese mice. • Weight loss during SAAR possibly involves altered β 3 -adrenergic signaling in brown adipose tissue. • SAAR effects require intact leptin signaling, being slightly attenuated in ob/ob mice and abolished in db/db mice. • During SAAR, leptin treatment preserves leptin sensitivity, promoting reduced food intake and weight loss in LFD-fed and ob/ob mice. Sulfur amino acid restriction (SAAR) paradoxically increases food intake while inducing weight loss, but the mechanisms underlying these outcomes remain unclear. To investigate the role of leptin in this response, we assessed food intake, body weight, and metabolic markers in diet-induced obese (DIO), leptin-deficient (ob/ob), and leptin receptor-deficient (db/db) mice. In DIO-SAAR mice, increased food intake was associated with hypothalamic upregulation of orexigenic (Agrp, Npy, and Mchr1) and downregulation of anorexigenic (Pomc, Cartpt, and Bdnf) mRNA levels. This orexigenic profile is accompanied by reduced adiposity and lower circulating leptin levels, suggesting that decreased leptin may induce compensatory increased food intake. Despite increased food intake, SAAR also induces weight loss, which is associated with enhanced β3-adrenergic signaling in brown and inguinal white AT (BAT and iWAT), as reflected by elevated Adrb3 and Ucp1 mRNA levels but downregulated protein expression, suggesting post-transcriptional regulation. These phenotypes induced by SAAR may possibly involve thyroid hormone metabolism, as indicated by increased circulating T3 and T4 concentrations and upregulation of BAT deiodinase 2 (D2) mRNA. Importantly, these metabolic effects of SAAR are attenuated in ob/ob and abolished in db/db mice, despite reductions in circulating SAA levels. Furthermore, leptin treatment during SAAR reduced food intake, induced weight loss, demonstrating preserved leptin sensitivity in low fat diet-fed and ob/ob mice. These findings reveal that leptin is required for both increased food intake and weight loss during SAAR.