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Curr Biol. 2019 Nov 5. pii: S0960-9822(19)31367-3. doi: 10.1016/j.cub.2019.10.027. [Epub ahead of print]

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

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Graduate Program in Neuroscience, University of Washington, Seattle, WA 98195, USA.
3
Scripps Center for Metabolomics, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
5
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA; Facultad de Medicina y Psicología, Universidad Autónoma de Baja California, Tijuana 22390, México.
6
Scripps Center for Metabolomics, The Scripps Research Institute, La Jolla, CA 92037, USA; Departments of Chemistry and Molecular Medicine, and Center for Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
7
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden. Electronic address: bconti@scripps.edu.

Abstract

Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost that 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 [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR is associated with increased hypothalamic levels of the endogenous opioid Leu-enkephalin, which is derived from the KOR agonist precursor dynorphin [11]. 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 independent of calorie intake. Similar results were seen with DIO mice subjected to CR. In contrast, inhibiting KOR did not change Tb in animals fed ad libitum (AL). Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, whereas chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nucleus 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.

KEYWORDS:

body temperature; body weight; calorie restriction; dieting; dynorphin; energy expenditure; energy homeostasis; hypothermia; kappa opioid receptor

PMID:
31786059
DOI:
10.1016/j.cub.2019.10.027

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