Scope
The aim of this study is to assess whether the long‐term addition of genistein to a high‐fat diet can ameliorate the metabolic and the cognitive alterations and whether the changes can be ...associated with modifications to the gut microbiota.
Methods and results
C57/BL6 mice were fed either a control (C) diet, a high‐fat (HF) diet, or a high‐fat diet containing genistein (HFG) for 6 months. During the study, indirect calorimetry, IP glucose tolerance tests, and behavioral analyses were performed. At the end of the study, plasma, liver, brain, and fecal samples were collected. The results showed that mice fed the HFG diet gained less weight, had lower serum triglycerides, and an improvement in glucose tolerance than those fed an HF diet. Mice fed the HFG diet also modified the gut microbiota that was associated with lower circulating levels of lipopolysaccharide (LPS) and reduced expression of pro‐inflammatory cytokines in the liver compared to those fed HF diet. The reduction in LPS by the consumption of genistein was accompanied by an improvement of the cognitive function.
Conclusions
Genistein is able to regulate the gut microbiota, reducing metabolic endotoxemia and decreasing the neuroinflammatory response despite the consumption of a HF diet.
Genistein is a dietary bioactive compound present in soy that has several health benefits. The present study reveals that genistein in mice fed a high‐fat diet is able to modify the gut microbiota by increasing the genus Prevotella and Akkermansia. This is accompanied by a decrease in circulating levels of lipopolysaccharide, reducing metabolic endotoxemia. As a consequence, there is a reduction in neuroinflammation, improving the cognitive function.
Nutrition and Atherosclerosis Torres, Nimbe; Guevara-Cruz, Martha; Velázquez-Villegas, Laura A ...
Archives of medical research,
07/2015, Letnik:
46, Številka:
5
Journal Article
Recenzirano
Cardiovascular disease (CVD) is a universal problem in modern society. Atherosclerosis is the leading cause of CVD resulting in high rate of mortality in the population. Nutrition science has focused ...on the role of essential nutrients in preventing deficiencies, at the present time, the nutritional strategies are crucial to promote health and intervene with these global noncommunicable diseases. In many cases, diet is a major driving force, which is much easier to change and follow than other factors. It is important to establish that the first strategy to treat atherosclerosis is to modify lifestyle habits, focusing on the beneficial properties of specific nutrients. In the last decades, epidemiological, clinical and experimental studies have demonstrated that diet plays a central role in the prevention of atherosclerosis. In this review we will focus on the effect of specific foods, nutrients and bioactive compounds, including epidemiological facts, potential mechanisms of action and dietary recommendations to reduce the risk of atherosclerosis. In particular, we include information about fiber, plant sterols and stanols, niacin, taurine, olive oil, omega 3 fatty acids, antioxidants, minerals, methyl nutrients and soy. In addition, we also show that dysbiosis of the intestinal microbiota associated with a consumption of certain animal food sources can generate some metabolites that are involved in the development of atherosclerosis and its consequences on CVD. According to the epidemiological, clinical and experimental studies we suggest a recommendation for some dietary foods, nutrients and bioactive compounds to support the complementary clinical management of patients with atherosclerosis.
Remodelling of energy storing white fat into energy expending beige fat could be a promising strategy to reduce adiposity. Here, we show that the bile acid-responsive membrane receptor TGR5 mediates ...beiging of the subcutaneous white adipose tissue (scWAT) under multiple environmental cues including cold exposure and prolonged high-fat diet feeding. Moreover, administration of TGR5-selective bile acid mimetics to thermoneutral housed mice leads to the appearance of beige adipocyte markers and increases mitochondrial content in the scWAT of Tgr5
mice but not in their Tgr5
littermates. This phenotype is recapitulated in vitro in differentiated adipocytes, in which TGR5 activation increases free fatty acid availability through lipolysis, hence fuelling β-oxidation and thermogenic activity. TGR5 signalling also induces mitochondrial fission through the ERK/DRP1 pathway, further improving mitochondrial respiration. Taken together, these data identify TGR5 as a druggable target to promote beiging with potential applications in the management of metabolic disorders.
Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and ...modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core‐clock gene Bmal1 within Gfap‐expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo‐caloric diet, under high‐fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER‐stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.
Main Points
The molecular clock in Gfap+ astrocytes modulate energy expenditure.
BMAL1 in Gfap+ astrocytes regulate BAT activity under DIO.
BMAL1 in Gfap+ astrocytes control transcriptional stress response in the VMH under DIO.
Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain
, yet ...their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs
and an established regulator of peripheral metabolism
. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.
SIRT7 is a NAD+‐dependent deacetylase that controls important aspects of metabolism, cancer, and bone formation. However, the molecular targets and functions of SIRT7 in the kidney are currently ...unknown. In silico analysis of kidney transcripts of the BXD murine genetic reference population revealed a positive correlation between Sirt7 and Slc12a7 mRNA expression, suggesting a link between the corresponding proteins that these transcripts encode, SIRT7, and the K‐Cl cotransporter KCC4, respectively. Here, we find that protein levels and activity of heterologously expressed KCC4 are significantly modulated depending on its acetylation status in Xenopus laevis oocytes. Moreover, SIRT7 interacts with KCC4 in a NAD+‐dependent manner and increases its stability and activity in HEK293 cells. Interestingly, metabolic acidosis increases SIRT7 expression in kidney, as occurs with KCC4. In contrast, total SIRT7‐deficient mice present lower KCC4 expression and an exacerbated metabolic acidosis than wild‐type mice during an ammonium chloride challenge. Altogether, our data suggest that SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, and reveals a novel role for SIRT7 in renal physiology.
SYNOPSIS
The molecular targets and functions of SIRT7 in the kidney are currently unknown. This study demonstrates that SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, and reveals a novel role for SIRT7 in renal physiology.
KCC4 protein levels and activity are modulated depending on its acetylation status.
SIRT7 interacts with KCC4 and increases its stability and activity through deacetylation.
Metabolic acidosis increased renal SIRT7 expression, while SIRT7‐deficient mice presented lower renal KCC4 expression.
SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, revealing a novel role for SIRT7 in renal physiology.
Genistein is an isoflavone present in soybeans and is considered a bioactive compound due to its widely reported biological activity. We have previously shown that intraperitoneal genistein ...administration and diet supplementation activates the thermogenic program in rats and mice subcutaneous white adipose tissue (scWAT) under multiple environmental cues, including cold exposure and high‐fat diet feeding. However, the mechanistic insights of this process were not previously unveiled. Uncoupling protein 1 (UCP1), a mitochondrial membrane polypeptide responsible for dissipating energy into heat, is considered the most relevant thermogenic marker; thus, we aimed to evaluate whether genistein regulates UCP1 transcription. Here we show that genistein administration to thermoneutral‐housed mice leads to the appearance of beige adipocyte markers, including a sharp upregulation of UCP1 expression and protein abundance in scWAT. Reporter assays showed an increase in UCP1 promoter activity after genistein stimulation, and in silico analysis revealed the presence of estrogen (ERE) and cAMP (CRE) response elements as putative candidates of genistein activation. Mutation of the CRE but not the ERE reduced genistein‐induced promoter activity by 51%. Additionally, in vitro and in vivo ChIP assays demonstrated the binding of CREB to the UCP1 promoter after acute genistein administration. Taken together, these data elucidate the mechanism of genistein‐mediated UCP1 induction and confirm its potential applications in managing metabolic disorders.
Genistein induces the thermogenic program in white adipose tissue via cAMP/PKA/CREB pathway to promote Ucp1 transcription. This mechanism of beige remodeling is independent of sympathetic nervous system activation.
Scope
Genistein increases whole body energy expenditure by stimulating white adipose tissue (WAT) browning and thermogenesis. G‐Coupled receptor GPR30 can mediate some actions of genistein, however, ...it is not known whether it is involved in the activation of WAT‐thermogenesis. Thus, the aim of the study is to determine whether genistein activates thermogenesis coupled to an increase in WAT browning and mitochondrial activity, in GPR30+/+ and GPR30−/− mice.
Methods and Results
GPR30+/+ and GPR30−/− mice are fed control or high fat sucrose diets containing or not genistein for 8 weeks. Body weight and composition, energy expenditure, glucose tolerance, and browning markers in WAT, and oxygen consumption rate, 3’, 5’‐cyclic adenosine monophosphate (cAMP) concentration and browning markers in adipocytes are evaluated. Genistein consumption reduces body weight and fat mass gain in a different extent in both genotypes, however, energy expenditure is lower in GPR30−/− compared to GPR30+/+ mice, accompanied by a reduction in browning markers, maximal mitochondrial respiration, cAMP concentration, and browning markers in cultured adipocytes from GPR30−/− mice. Genistein improves glucose tolerance in GPR30+/+, but this is partially observed in GPR30−/− mice.
Conclusion
The results show that GPR30 partially mediates genistein stimulation of WAT thermogenesis and the improvement of glucose tolerance.
Genistein increases 3’, 5’‐cyclic adenosine monophosphate (cAMP) concentration and the abundance of thermogenic genes in adipocytes, increasing mitochondrial activity and stimulating energy expenditure in adipose tissue in GPR30+/+ mice, and also improving insulin sensitivity through an increase in AMP‐activated protein kinase (AMPK) phosphorylation in skeletal muscle. These effects are partially decreased by the lack of the GPR30 receptor.
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over ...the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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.
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