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Activation of hypothalamic AMPK ameliorates metabolic complications of experimental arthritis. OBJECTIVE: To investigate whether thermogenesis and the hypothalamus may be involved in the physiopathology of experimental arthritis (EA). METHODS: EA was induced in Lewis male rats by intradermal injection of Freund's complete adjuvant (FCA). Food intake, body weight, plasma cytokines, thermographic analysis, gene and protein expression of thermogenic markers in brown (BAT) and white (WAT) adipose tissue and hypothalamic AMP-activated protein kinase (AMPK) were analyzed. Virogenetic activation of hypothalamic AMPK was performed. RESULTS: We first demonstrate that EA is associated with increased BAT thermogenesis and browning of subcutaneous WAT (sWAT) leading to elevated energy expenditure. Moreover, rats suffering EA show inhibition of hypothalamic AMPK, a canonical energy sensor modulating energy homeostasis at central level. Notably, specific genetic activation of AMPK in the ventromedial nucleus of the hypothalamus (VMH; a key site modulating energy metabolism) reverses the effect of EA on energy balance, brown fat and browning, as well as promoting an amelioration of the inflammatory status. CONCLUSION: Overall, these data indicate that EA promotes a central catabolic state that can be targeted and reversed by the activation of hypothalamic AMPK. This might open new therapeutic alternatives to treat rheumatoid arthritis (RA)-associated metabolic comorbidities, improving RA-patients overall prognosis.