exposure . 5 6 Running Title : Examination of Neuronal PTP 1 B in Cold - Induced Thermogenesis 7 8 9

26 The adipose tissue-derived hormone, leptin, regulates energy balance through catabolic 27 effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin 28 activation of POMC neurons increases thermogenesis and locomotor activity. Protein 29 tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling. 30 POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet31 induced body weight and adiposity gain due to increased energy expenditure and greater 32 leptin sensitivity. Mice lacking the leptin gene (ob/ob mice) are hypothermic and cold33 intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased 34 sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC 35 PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating 36 food intake, body weight, core temperature (TC) and spontaneous physical activity (SPA) 37 in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC38 Ptp1b-deficient mice compared to wild type controls. POMC-Ptp1b mice were 39 hypersensitive to leptin-induced food intake and body weight suppression compared to 40 wild types, yet they displayed similar leptin-induced increases in TC. Interestingly, 41 POMC-Ptp1b mice had increased BAT weight and elevated plasma triiodothyronine 42 (T3) levels in response to a 4-day cold challenge, as well as reduced SPA at 24 hours 43 after cold exposure, relative to controls. These data show that PTP1B in POMC neurons 44 plays a role in short-term cold-induced reduction of spontaneous physical activity, and 45 may influence cold-induced thermogenesis via enhanced activation of the thyroid axis. 46