Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. ...Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.
Hyperplastic expansion of white adipose tissue (WAT) relies in part on the proliferation of adipocyte precursor cells residing in the stromal vascular cell fraction (SVF) of WAT. This study reveals a ...circadian clock- and feeding-induced diurnal pattern of cell proliferation in the SVF of visceral and subcutaneous WAT in vivo, with higher proliferation of visceral adipocyte progenitor cells subsequent to feeding in lean mice. Fasting or loss of rhythmic feeding eliminates this diurnal proliferation, while high fat feeding or genetic disruption of the molecular circadian clock modifies the temporal expression of proliferation genes and impinges on diurnal SVF proliferation in eWAT. Surprisingly, high fat diet reversal, sufficient to reverse elevated SVF proliferation in eWAT, was insufficient in restoring diurnal patterns of SVF proliferation, suggesting that high fat diet induces a sustained disruption of the adipose circadian clock. In conclusion, the circadian clock and feeding simultaneously impart dynamic, regulatory control of adipocyte progenitor proliferation, which may be a critical determinant of adipose tissue expansion and health over time.
Scope
Circadian rhythm is an endogenous and self‐sustained timing system, responsible for the coordination of daily processes in 24‐h timescale. It is regulated by an endogenous molecular clock, ...which is sensitive to external cues as light and food. This study has previously shown that grape seed proanthocyanidins extract (GSPE) regulates the hepatic molecular clock. Moreover, GSPE is known to interact with some microRNAs (miRNAs). Therefore, the aim of this study is to evaluate if the activity of GSPE as modulator of hepatic clock genes can be mediated by miRNAs.
Methods and results
250 mg kg−1 of GSPE is administered to Wistar rats before a 6‐h jet lag and sacrificed at different time points. GSPE modulated both expression of Bmal1 and miR‐27b‐3p in the liver. Cosinor‐based analysis reveals that both Bmal1 and miR‐27b‐3p expression follow a circadian rhythm, a negative interaction between them, and the role of GSPE adjusting the hepatic peripheral clock via miRNA. Additionally, in vitro studies show that Bmal1 is sensitive to GSPE (25 mg L−1). However, this effect is independent of miR‐27b‐3p.
Conclusion
miRNA regulation of peripheral clocks via GSPE may be part of a complex mechanism that involves the crosstalk with the central system rather than a direct effect.
Jet‐lagged rats and HepG2 cells were used to evaluate if the activity of grape seed proanthocyanidins extract (GSPE) as modulator of hepatic clock genes is mediated by miRNAs. GSPE modulates expression of hepatic Bmal1 and miR‐27b‐3p. Moreover, cosinor‐based analysis reveals that both Bmal1 and miR‐27b‐3p expression follow a circadian rhythm and that GSPE adjusted the hepatic peripheral clock via miRNA.
Adipose tissue (AT) is comprised of a diverse number of cell types, including adipocytes, stromal cells, endothelial cells, and infiltrating leukocytes. Adipose stromal cells (ASCs) are a mixed ...population containing adipose progenitor cells (APCs) as well as fibro-inflammatory precursors and cells supporting the vasculature. There is growing evidence that the ability of ASCs to renew and undergo adipogenesis into new, healthy adipocytes is a hallmark of healthy fat, preventing disease-inducing adipocyte hypertrophy and the spillover of lipids into other organs, such as the liver and muscles. However, there is building evidence indicating that the ability for ASCs to self-renew is not infinite. With rates of ASC proliferation and adipogenesis tightly controlled by diet and the circadian clock, the capacity to maintain healthy AT via the generation of new, healthy adipocytes appears to be tightly regulated. Here, we review the contributions of ASCs to the maintenance of distinct adipocyte pools as well as pathogenic fibroblasts in cancer and fibrosis. We also discuss aging and diet-induced obesity as factors that might lead to ASC senescence, and the consequences for metabolic health.
Abstract Background While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, ...insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. Scope of review This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively, can destroy synchrony between peripheral clocks and the central pacemaker in the brain as well as between peripheral clocks themselves. In addition, we review several studies looking at clock gene SNPs in humans and the metabolic phenotypes or tendencies associated with particular clock gene mutations. Major conclusions Targeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors). Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future.
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options ...for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon‐Like Receptor Like 1 (ARNTL, or Bmal1) and the liver‐enriched nuclear factor 4 alpha (HNF4α) are robustly co‐expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α– either by isoform switching, or loss of expression‐ results in an increased risk for HCC, while BMAL1 gain‐of‐function in HNF4α‐positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen‐induced liver injury and in the “STAM” model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α‐deficient, BMAL1‐positive HCC with REV‐ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV‐ERB‐dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.
Scope
One major health problem in westernized countries is dysregulated fatty acid and cholesterol metabolism that causes pathologies such as metabolic syndrome. Previous studies from our group have ...shown that proanthocyanidins, which are the most abundant polyphenols in the human diet, regulate lipid metabolism and are potent hypolipidemic agents. The noncoding RNAs, miR‐33 and miR‐122, regulate genes that are involved in lipid metabolism.
Methods and results
Here, we show that grape seed proanthocyanidins rapidly and transiently repressed the expression of miR‐33 and miR‐122 in rat hepatocytes in vivo and in vitro. Furthermore, the miR‐33 target gene ATP‐binding cassette A1 and the miR‐122 target gene fatty acid synthase were also modulated by proanthocyanidins. Specifically, ATP‐binding cassette A1 mRNA and protein levels were increased, and fatty acid synthase mRNA and protein levels were reduced after the miRNA levels were altered.
Conclusion
These results suggest that proanthocyanidin treatment increased hepatic cholesterol efflux to produce new HDL particles by repressing miR‐33, and it reduced lipogenesis by repressing miR‐122. These results highlight a new mechanism by which grape seed proanthocyanidins produce hypolipidemia through their effects on miRNA modulators of lipid metabolism.
SCOPE: Circadian rhythms allow organisms to anticipate and adapt to environmental changes, and food components can adjust internal rhythms. Proanthocyanidins improve cardiovascular risk factors that ...exhibit circadian oscillations. Therefore, the aim of the current study was to determine whether proanthocyanidins can modulate body rhythms. METHODS AND RESULTS: Male Wistar rats were orally gavaged with 250 mg grape seed proanthocyanidin extract (GSPE)/kg body weight at zeitgeber time (ZT) 0 (light on). Phenotypic biorhythm was evaluated by measuring the concentration of plasma melatonin and metabolites, using MNR‐metabolomics, at several ZT. Remarkably, GSPE treatment maintained nocturnal melatonin levels at ZT3 and altered the oscillations of some metabolites in plasma. Quantification of expression of clock‐core (Clock, Bmal1, Per2, Rorα, Rev‐erbα) and clock‐controlled (Nampt) genes in the hypothalamus by RT‐PCR showed that this phenotypic alteration was concomitant with the modulation of the expression pattern of Bmal1 and Nampt. However, GSPE did not modulate the nocturnal expression of clock genes when administered at ZT12 (light off). CONCLUSION: PAs could have chronobiological properties, although their activity depends largely on the time of administration.
White adipose tissue (WAT) is a metabolic organ with flexibility to retract and expand based on energy storage and utilization needs, processes that are driven via the coordination of different cells ...within adipose tissue. WAT is comprised of mature adipocytes (MA) and cells of the stromal vascular cell fraction (SVF), which include adipose progenitor cells (APCs), adipose endothelial cells (AEC) and infiltrating immune cells. APCs have the ability to proliferate and undergo adipogenesis to form MA, the main constituents of WAT being predominantly composed of white, triglyceride-storing adipocytes with unilocular lipid droplets. While adiposity and adipose tissue health are controlled by diet and aging, the endogenous circadian (24-h) biological clock of the body is highly active in adipose tissue, from adipocyte progenitor cells to mature adipocytes, and may play a unique role in adipose tissue health and function. To some extent, 24-h rhythms in adipose tissue rely on rhythmic energy intake, but individual circadian clock proteins are also thought to be important for healthy fat. Here we discuss how and why the clock might be so important in this metabolic depot, and how temporal and qualitative aspects of energy intake play important roles in maintaining healthy fat throughout aging.
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