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Time-of-day defines NAD⁺ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.

ABSTRACT: The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD⁺. Increasing NAD⁺ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD⁺ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD⁺ treatment for diet-induced metabolic disease in mice. Increasing NAD⁺ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD⁺ immediately before the rest phase selectively compromised these responses. Remarkably, timed NAD⁺ adjusted circadian oscillations of the liver clock until completely inverting its oscillatory phase when increased just before the rest period, resulting in misaligned molecular and behavioral rhythms in male and female mice. Our findings unveil the time-of-day dependence of NAD⁺-based therapies and support a chronobiology-based approach.

SUBMITTER: Escalante-Covarrubias Q

PROVIDER: S-EPMC10043291 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Time-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.

Escalante-Covarrubias Quetzalcoatl Q Mendoza-Viveros Lucía L González-Suárez Mirna M Sitten-Olea Román R Velázquez-Villegas Laura A LA Becerril-Pérez Fernando F Pacheco-Bernal Ignacio I Carreño-Vázquez Erick E Mass-Sánchez Paola P Bustamante-Zepeda Marcia M Orozco-Solís Ricardo R Aguilar-Arnal Lorena L

Nature communications 20230327 1

The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD+. Increasing NAD+ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD+ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ treatment for diet ...[more]

PMID: 36973248

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Project description:BackgroundDaily cyclic changes in environmental conditions are key signals for anticipatory and adaptive adjustments of most living species, including mammals. Lower ambient temperature stimulates the thermogenic activity of brown adipose tissue (BAT) and skeletal muscle. Given that the molecular components of the endogenous biological clock interact with thermal and metabolic mechanisms directly involved in the defense of body temperature, the present study evaluated the differential homeostatic responses to a cold stimulus at distinct time-windows of the light/dark-cycle.MethodsMale Wistar rats were subjected to a single episode of 3 h cold ambient temperature (4°C) at one of 6 time-points starting at Zeitgeber Times 3, 7, 11, 15, 19, and 23. Metabolic rate, core body temperature, locomotor activity (LA), feeding, and drinking behaviors were recorded during control and cold conditions at each time-point. Immediately after the stimulus, rats were euthanized and both the soleus and BAT were collected for real-time PCR.ResultsDuring the light phase (i.e., inactive phase), cold exposure resulted in a slight hyperthermia (p < 0.001). Light phase cold exposure also increased metabolic rate and LA (p < 0.001). In addition, the prevalence of fat oxidative metabolism was attenuated during the inactive phase (p < 0.001). These metabolic changes were accompanied by time-of-day and tissue-specific changes in core clock gene expression, such as DBP (p < 0.0001) and REV-ERBα (p < 0.01) in the BAT and CLOCK (p < 0.05), PER2 (p < 0.05), CRY1 (p < 0.05), CRY2 (p < 0.01), and REV-ERBα (p < 0.05) in the soleus skeletal muscle. Moreover, genes involved in substrate oxidation and thermogenesis were affected in a time-of-day and tissue-specific manner by cold exposure.ConclusionThe time-of-day modulation of substrate mobilization and oxidation during cold exposure provides a clear example of the circadian modulation of physiological and metabolic responses. Interestingly, after cold exposure, time-of-day mostly affected circadian clock gene expression in the soleus muscle, despite comparable changes in LA over the light-dark-cycle. The current findings add further evidence for tissue-specific actions of the internal clock in different peripheral organs such as skeletal muscle and BAT.

Project description:BackgroundNicotinamide adenine dinucleotide (NAD+) is a coenzyme and plays a crucial role in several metabolic processes. This study explored the association of nicotinamide adenine dinucleotide (NAD+) levels with metabolic disease (MD) in adults.MethodsIn this cross-sectional study, all data were collected from the Jidong community. MD was defined as the presence of one or more of the following disease components: hypertension, dyslipidemia, diabetes, hyperuricemia, obesity, and non-alcoholic fatty liver disease (NAFLD). The MD components were categorized into three groups: those with one component, those with two components, and those with three to six components. The whole blood NAD+ level was measured using a cycling assay and LC-MS/MS analysis. The participants were divided into four groups based on their NAD+ level quartiles. Multivariable logistic regression was used to evaluate the association of the whole blood NAD+ levels with MD.ResultsOf the 1,394 eligible participants, the average age was 43.2 years, and 74.3% had MD. In the top quartile of NAD+, the prevalence of MD and each of its components (hypertension, hyperlipidemia, diabetes, hyperuricemia, obesity, and NAFLD) were 87.9% 35.2%, 62.3%, 8.7%, 36.9%, 21.0%, and 60.5%, respectively. As compared with the lowest NAD+ quartile (≤29.4 μmol/L), the adjusted odds ratios and 95% confidence interval of the highest quartile were 3.01 (1.87-4.87) for MD, 2.48 (1.44-4.29) for 1 MD component, 2.74 (1.45-5.17) for 2 MD components, and 4.30 (2.32-7.98) for 3-6 MD components. The risk of MD began to increase at NAD+ levels of 31.0 μmol/L, as revealed by the gradient associations of NAD+ levels with MD. There was no significant interaction between age, sex, drinking, smoking, and NAD+ for MD (p for interaction ≥0.10).ConclusionsIncreased NAD+ was significantly associated with MD, as well as its individual components. Our findings provide new evidence for the relationship between blood NAD+ levels and MD.

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Time-of-day defines NAD⁺ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.

Publications

Time-of-day defines NAD<sup>+</sup> efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.

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