Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss

Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost which is sustainable if adequate calorie intake is maintained. When nutrients are scarce or experimentally reduced such as during calorie restriction (CR), endotherms can reduce energy expenditure by lowering Tb. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR was associated with increased hypothalamic levels of the endogenous opioid leu-enkephalin; which it is derived from KOR agonist precursor, dynorphin and pharmacological inhibition of KOR, but not of the delta or the mu opioid receptor subtypes, fully blocked CR-induced hypothermia and increased weight loss during CR independently of calorie intake. Similar results were seen with diet-induced, obese mice subjected to CR. Conversely, inhibiting KOR did not change Tb in animals fed ad libitumM. Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, while chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nuclei lowered Tb. These data indicate that KOR signaling is a pivotal regulator of energy homeostasis and can affect body weight during dieting by modulating Tb and energy expenditure.