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

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.

SUBMITTER: Cintron-Colon R

PROVIDER: S-EPMC6917995 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Cintron-Colon Rigo R Johnson Christopher W CW Montenegro-Burke J Rafael JR Guijas Carlos C Faulhaber Lila L Sanchez-Alavez Manuel M Aguirre Carlos A CA Shankar Kokila K Singh Mona M Galmozzi Andrea A Siuzdak Gary G Saez Enrique E Conti Bruno B

Current biology : CB 20191127 24

Mammals maintain a nearly constant core body temperature (T<sub>b</sub>) 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 T<sub>b</sub> [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Her ...[more]

PMID: 31786059

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Project description:Background:Mathematical models have been developed to predict body weight (BW) and composition changes in response to lifestyle interventions, but these models have not been adequately validated over the long term. Objective:We compared mathematical models of human BW dynamics underlying 2 popular web-based weight-loss prediction tools, the National Institutes of Health Body Weight Planner (NIH BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC WLP), with data from the 2-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study. Design:Mathematical models were initialized using baseline CALERIE data, and changes in body weight (?BW), fat mass (?FM), and energy expenditure (?EE) were simulated in response to time-varying changes in energy intake (?EI) objectively measured using the intake-balance method. No model parameters were adjusted from their previously published values. Results:The PBRC WLP model simulated an exaggerated early decrease in EE in response to calorie restriction, resulting in substantial underestimation of the observed mean (95% CI) BW losses by 3.8 (3.5, 4.2) kg. The NIH WLP simulations were much closer to the data, with an overall mean ?BW bias of -0.47 (-0.92, -0.015) kg. Linearized model analysis revealed that the main reason for the PBRC WLP model bias was a parameter value defining how spontaneous physical activity expenditure decreased with caloric restriction. Both models exhibited substantial variability in their ability to simulate individual results in response to calorie restriction. Monte Carlo simulations demonstrated that ?EI measurement uncertainties were a major contributor to the individual variability in NIH BWP model simulations. Conclusions:The NIH BWP outperformed the PBRC WLP and accurately simulated average weight-loss and energy balance dynamics in response to long-term calorie restriction. However, the substantial variability in the NIH BWP model predictions at the individual level suggests cautious interpretation of individual-level simulations. This trial was registered at clinicaltrials.gov as NCT00427193.

Project description:BackgroundAlthough preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies.ObjectiveWe conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen.DesignOne hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) ≥25 to <40, 50% women], aged 35-65 y, were randomly assigned to an ICR group (5 d without energy restriction and 2 d with 75% energy deficit, net weekly energy deficit ∼20%), a CCR group (daily energy deficit ∼20%), or a control group (no advice to restrict energy) and participated in a 12-wk intervention phase, a 12-wk maintenance phase, and a 26-wk follow-up phase.ResultsLoge relative weight change over the intervention phase was -7.1% ± 0.7% (mean ± SEM) with ICR, -5.2% ± 0.6% with CCR, and -3.3% ± 0.6% with the control regimen (Poverall < 0.001, PICR vs. CCR = 0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was -5.2% ± 1.2% with ICR, -4.9% ± 1.1% with CCR, and -1.7% ± 0.8% with the control regimen (Poverall = 0.01, PICR vs. CCR = 0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers.ConclusionOur results on the effects of the "5:2 diet" indicate that ICR may be equivalent but not superior to CCR for weight reduction and prevention of metabolic diseases. This trial was registered at clinicaltrials.gov as NCT02449148.

Dataset Information

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

Publications

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

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