Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2° C for several hours. Mice lacking TIP39 signaling, either because of PTH2R null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature.

Dopamine (DA), norepinephrine (NE) and serotonin (5‐HT) modulate feeding behavior and energy homeostasis. Here, we investigated effects of sibutramine (Sib), duloxetine (Dlx), and atomoxetine (Atx) on acute food intake (FI), daily FI and body weight (BW) gain over 28 d in diet‐induced obese (DIO) mice. Sib is a balanced reuptake inhibitor at transporters for DA (DAT), 5‐HT (SERT) and NE (NET), whereas Dlx and Atx are selective for SERT and NET, respectively. Mice, fed a high fat diet for 12 wk, weighed 40–44 g prior to receiving chronic twice daily oral dosing for 28 d. FI, BW, serum leptin levels and weight of adipose tissue were measured and compared to free concentrations of compounds in serum and brain. Sib (1–10 mg/kg), Dlx (3–30 mg/kg) and Atx (3–30 mg/kg) dose‐dependently decreased food intake 4 and 8 hr after a single dose (hypophagia rank order of potency: Sib = Dlx > Atx). From 7 – 28 d, daily FI was equivalent in all groups of mice. At the highest doses tested, BW decreased significantly in Sib‐ and Atx‐treated mice at day 28 (~10% compared to vehicle), whereas BW was unchanged by the end of chronic Dlx treatment. On day 29, all compounds decreased serum leptin levels. Atx‐induced decrease in BW was accompanied by a reduction in total brown adipose tissue. These results suggest that the balance of activity at DAT, SERT and NET differentially influences acute hypophagia, energy expenditure and sustained weight loss.