Thyrotropin-releasing hormone neurons of different hypothalamic nuclei increase energy expenditure

Several neuronal populations in the hypothalamus and brainstem express thyrotropin-releasing hormone (TRH). While TRH neurons in the paraventricular nucleus (PVN) regulate the thyroid axis, the roles of other TRH-producing neurons remain largely unknown. Here we investigate the role of TRH neurons in the PVN, the dorsomedial hypothalamus (DMH), the medial preoptic area (MPA), and the rostral raphe pallidus (RPa) for metabolism in mice. Selective activation of these populations using chemogenetics in mice revealed that TRH neurons of the hypothalamus increase food intake and influence energy homeostasis in different ways. Specifically, TRH neurons in the PVN and DMH enhance brown adipose tissue activity via a polysynaptic circuit, while MPA-located neurons increase locomotor activity and maintain cold tolerance. These effects were independent of the thyroid axis, demonstrating that TRH neurons have distinct, subtype-specific ways to increase energy expenditure beyond regulating the thyroid axis in mice.