The preoptic area (POA) of the hypothalamus has garnered attention regarding its pivotal role in energy balance control and thermoregulation. Activation or inhibition of specific POA neurons has been shown to affect body temperature, locomotor activity and energy expenditure. To gain novel insights into this regulatory mechanism, we have conducted a comprehensive analysis of a distinct neuronal cluster within the POA that express the neuropeptide prepronociceptin (PNOC). Using chemogenetic techniques, we selectively activated PNOC(POA) neurons of mice and observed a significant reduction in brown adipose tissue (BAT) temperature and energy expenditure. Further examination of PNOC(POA) neuronal projections unveiled robust connectivity to various brain regions involved in autonomic control, including the dorsomedial hypothalamus (DMH), a key relay in BAT thermogenesis regulation. Ablating PNOC(POA) neurons led to a chronic increase of BAT thermogenesis correlated with weight loss as well as an increase in core body temperature. Interestingly, the activation of PNOC(POA) neurons initiated an acute inflammatory response in BAT, characterized by upregulation of immediate early genes associated with inflammation and chemotaxis. On the contrary, the ablation of PNOC(POA) neurons lead to upregulation of Irisin and Apelin in BAT, well-known for their contributions to enhancing thermogenesis and exerting anti-inflammatory effects.While research has focused on investigating hypothalamic circuits, there has been limited exploration of the interaction between hypothalamic neurons and innervated tissues, such as brown adipose tissue. By unraveling the regulatory mechanisms that are governed by PNOC(POA) neurons, we can better understand the neural control of whole-body energy expenditure and adipose tissue function.