Regulation of Hypothalamic Signaling by Tuberoinfundibular Peptide of 39 Residues Is Critical for the Response to Cold: A Novel Peptidergic Mechanism of Thermoregulation

Abstract

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.

Neurochemical Assessment and Behavioral Role of Tuberoinfundibular Peptide-39 in Acute Restraint Stress-Induced Depression in Rats.

“…These reports point toward the importance of TIP39 in regulating the glutaminergic and GABAergic system. However, our study report supports the previous study implicated that TIP39 peptide can regulate hypothalamic glutaminergic and inhibitory GABAergic neuron in the cerebral region [28]. Recent studies have reported that, besides the limbic area, TIP39 is abundantly expressed in other brain regions also [29].…”

Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

“…Since sympathetic BAT thermogenesis is augmented by skin cooling (Nakamura and Morrison, 2007) or direct cooling of the POA, by brain transections immediately caudal to the POA, and by local inhibition of POA neuronal activity (Yoshida et al, 2009), warm-sensitive POA neurons are postulated to integrate cutaneous and core thermal signals and to provide a GABAergic inhibitory input to BAT sympathoexcitatory neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHA) and/or the rRPa (Dimitrov et al, 2011; Nakamura et al, 2009; Yoshida et al, 2009). The MnPO also contains glutamatergic neurons that project to the DMH/DHA, that are synaptically connected to BAT, and that receive glutamatergic terminals containing tuberoinfundibular peptide of 39 residues (TIP39), which produces an increase in core temperature when injected into the MnPO (Dimitrov et al, 2011). MnPO neurons expressing the leptin receptor (LepRb) also project to DMH/DA (Zhang et al, 2011a).…”

“…PGE 2 , synthesized in the brain vasculature and in peripheral tissues, is a powerful endogenous pyrogenic mediator that binds to EP3 receptors in the POA (Lazarus et al, 2007; Nakamura et al, 2002) and produces an activation of BAT thermogenesis (Madden and Morrison, 2003; Nakamura et al, 2002) by inhibiting the POA warm-sensitive, GABAergic inhibition (Lundius et al, 2010; Nakamura et al, 2002; Yoshida et al, 2003) of BAT sympathoexcitatory neurons in DMH/DHA (Nakamura et al, 2002; Nakamura et al, 2005) and potentially in the rRPa (Nakamura et al, 2004; Nakamura et al, 2009). Potential sources of the glutamatergic drive to DMH/DA neurons supporting the febrile activation of BAT thermogenesis include glutamatergic neurons in the MnPO (Dimitrov et al, 2011) and orexin/glutamatergic neurons in perifornical lateral hypothalamus (PeF/LH) (Takahashi et al, 2013). …”

“…1) is reduced, glutamatergic inputs to BAT sympathoexcitatory neurons in the DMH/DA, including many expressing LepRb, provide the synaptic drive essential for stimulation of BAT SNA and BAT thermogenesis (Cano et al, 2003; Madden and Morrison, 2004; Nakamura and Morrison, 2007; Nakamura et al, 2005; Rathner and Morrison, 2006; Sarkar et al, 2007; Yoshida et al, 2009; Zhang et al, 2011a). The excitatory inputs to DMH/DHA could include the MnPO (Dimitrov et al, 2011); the PeF/LH (Takahashi et al, 2013) and the periaqueductal gray (PAG) (de Menezes et al, 2009). A role for the melanocortin 4 receptor (MC4-R) in the DMH in the regulation of BAT is supported by increased BAT UCP-1 mRNA after injection of the MC4-R agonist, MTII, in DMH and attenuation of systemic MTII-evoked increases in TBAT by injection of an MC4-R antagonist in DMH (Enriori et al, 2011).…”

Neural Control of Energy Expenditure

“…However, stimulatory glutamatergic inputs to the DMH/DHA have been proposed as well (Madden and Morrison 2004), and cold-sensitive glutamatergic POA neurons may provide these inputs (Dimitrov et al 2011). Because there are also warm-activated cholinergic neurons in the DMH that directly inhibit thermogenic RMR neurons (Jeong et al 2015), the POA is very likely to contain warm-sensitive glutamatergic neurons that directly innervate these DMH neurons.…”