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Circadian rhythms of hormone secretion and obesity

World Journal of Diabetes 2018年第11期9卷 195-198页

作者： rajendra raghow Department of Veterans Affairs Medical Center MemphisTN 38104United States Department of Pharmacology University of Tennessee Health Science CenterMemphisTN 38163United States

The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor(PPAR) γ(key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARγ in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing's disease.

关键词： Circadian rhythms Glucocorticoids Adipose tissue Pre-adipocytes Stem cells Terminal differentiation

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Statins redux:A re-assessment of how statins lower plasma cholesterol

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World Journal of Diabetes 2017年第6期8卷 230-234页

作者： rajendra raghow Department of Veterans Affairs Medical Center Department of Pharmacology University of Tennessee Health Science CenterMemphisTN 38163United States

Obesity associated dyslipidemia and its negative effects on the heart and blood vessels have emerged as a major healthcare challenge around the globe. The use of statins, potent inhibitors of hydroxyl-methyl glutaryl (HMG) Co-A reductase, a rate-limiting enzyme in cholesterol biosynthesis, has significantly reduced the rates of cardiovascular and general mortality in patients with coronary artery disease. How statins lower plasma cholesterol levels presents a mechanistic conundrum since persistent exposure to these drugs in vitro or in vivo is known to induce overexpression of the HMG Co-A reductase gene and protein. In an attempt to solve this mechanistic puzzle, Schonewille et al, studied detailed metabolic parameters of cholesterol synthesis, inter-organ flux and excretion in mice treated with 3 common statins, rosuvastatin, atorvastatin or lovastatin, each with its unique pharmacokinetics. From the measurements of the rates of heavy water (D2O) and [13C]-acetate incorporation into lipids, the authors calculated the rates of whole body and organ-specific cholesterol synthesis in control and statin-treated mice. These analyses revealed dramatic enhancement in the rates of hepatic cholesterol biosynthesis in statin-treated mice that concomitantly elicited lower levels of cholesterol in their plasma. The authors have provided strong evidence to indicate that statin treatment in mice led to induction of compensatory metabolic pathways that apparently mitigated an excessive accumulation of cholesterol in the body. It was noted however that changes in cholesterol metabolism induced by 3 statins were not identical. While sustained delivery of all 3 statins led to enhanced rates of biliary excretion of cholesterol and its fecal elimination, only atorvastatin treated mice elicited enhanced trans-intestinal cholesterol excretion. Thus, blockade of HMGCR by statins in mice was associated with profound metabolic adaptations that reset their cholesterol

关键词： Statins Atorvastatin Lovastatin Rosuvastatin Cholesterol synthesis Hydroxyl-methyl glutaryl-CoA reductase

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Gut-brain crosstalk regulates craving for fatty food

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World Journal of Diabetes 2017年第12期8卷 484-488页

作者： rajendra raghow Department of Veterans Affairs Medical Center Department of Pharmacology University of Tennessee Health Science CenterMemphisTN 38163United States

Patients undergoing Roux-en-Y gastric bypass(RYGB)surgery elicit striking loss of body weight. Anatomical restructuring of the gastrointestinal(GI) tract, leading to reduced caloric intake and changes in food preference, are thought to be the primary drivers of weight loss in bariatric surgery patients. However, the mechanisms by which RYGB surgery causes a reduced preference for fatty foods remain elusive. In a recent report, Hankir et al described how RYGB surgery modulated lipid nutrient signals in the intestine of rats to blunt their craving for fatty food. The authors reported that RYGB surgery restored an endogenous fat-satiety signaling pathway, mediated via oleoylethanolamide(OEA), that was greatly blunted in obese animals. In RYGB rats, high fat diet(HFD) led to increased production of OEA that activated the intestinal peroxisome proliferation activator receptors-α(PPARα). In RYGB rats, activation of PPARα by OEA was accompanied by enhanced dopamine neurotransmission in the dorsal striatum and reduced preference for HFD. The authors showed that OEA-mediated signals to the midbrain were transmitted via the vagus nerve. Interfering with either the production of OEA in enterocytes, or blocking of vagal and striatal D1 receptors signals eliminated the decreased craving for fat in RYGB rats. These studies demonstrated that bariatric surgery led to alterations in the reward circuitry of the brain in RYGB rats and reduced their preference for HFD.

关键词： Roux-en-Y gastric bypass surgery Dietary lipids Dopamine D1 receptors Peroxisome proliferator activated receptor-alpha Oleoylethanolamide

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Bariatric surgery-mediated weight loss and its metabolic consequences for type-2 diabetes

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World Journal of Diabetes 2013年第3期4卷 47-50页

The worldwide epidemic of obesity and its medical complications are being dealt with a combination of life style changes(e.g.,healthier diet and exercise),medications and a variety of surgical *** Roux-en Y gastric bypass(RYGB) and laparoscopic adjustable gastric banding(LAGB) are two of the most common weight loss surgeries for morbid obesityassociated metabolic syndrome and insulin resistance.A vast majority of patients that undergo RYGB and LAGB are known to experience marked weight loss and attenuation of diabetes.A number of recent studies have indicated that the rates of remission in glycemic control and insulin sensitivity are significantly greater in patients that have undergone RYGB.A plausible hypothesis to explain this observation is that the gastric bypass surgery as opposed to the gastric banding procedure impinges on glucose homeostasis by a weight loss-independent *** a recent paper,Bradley et al have experimentally explored this *** authors compared several clinical and laboratory parameters of insulin sensitivity and β-cell function in cohorts of RYGB and LAGB patients before and after they lost approximately 20% of their body *** loss,both groups of patients underwent similar changes in their intra-abdominal and total adipose tissue volume,hepatic triglyceride and circulating leptin *** RYGB patients who lost 20% body mass,manifested higher postprandial output of glucose,insulin and glucagon-like peptide-1;these laboratory parameters remained unchanged in LABG *** of the observed differences in transient responses of RYGB and LAGB patients to mixed meal,the overall glycemic control as judged by glucose tolerance,multi-organ insulin sensitivity and β-cell function were nearly identical in the two *** RYGB and LAGB patient cohorts also experienced similar changes in the expression of a number of pro-and anti-inflammatory *** on these analyses,Bradley et al concl

关键词： Bariatric surgery Roux-en Y gastric bypass Laparoscopic adjustable gastric banding Weight loss Type-2 diabetes

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Gestational nutrition and the development of obesity during adulthood

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World Journal of Diabetes 2012年第11期3卷 178-181页

作者： rajendra raghow Department of Veterans Affairs Medical Center Memphis TN 38104 United States Department of Pharmacology University of Tennessee Health Science CenterMemphis TN 38163United States

Recent epidemiological studies indicate a strong linkbetween intrauterine under-nutrition and propensityof such off spring for developing obesity and meta-bolic syndrome in later life. Garg et al investigated the mechanistic basis of this phenomenon and its potential reversibility in rats. The authors found that rats experiencing gestational under-nutrition but fed normally after birth (IUGR) gained body mass with excessive subcutaneous and visceral fat. The IUGR rats were alsome tabolically inflexible since they showed similar rates of energy expenditure and O2consumption in the fedand fasted states. However, if such pups were food-restricted during lactation (PNGR), their metabolic profiles resembled those of control and IPGR (subject tofood restriction during pre- and postnatal periods) ***, postnatal caloric restriction superimposed on intrauterine under nutrition significantly improved insulinsensitivity and adiposity of rats that would otherwise develop metabolic inflexibility and visceral obesity. The observations of Garg et al , have serious implications interm of the design of the future experimental studiesas well as their clinical translation in humans.

关键词： Intrauterine under-nutrition Metabolic plas-ticity Type 2 diabetes Metabolic syndrome Caloric restriction

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Betatrophin:A liver-derived hormone for the pancreatic β-cell proliferation

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World Journal of Diabetes 2013年第6期4卷 234-237页

The pancreaticβ-cell failure which invariably accompanies insulin resistance in the liver and skeletal muscle is a hallmark of type-2 diabetes mellitus(T2DM).The persistent hyperglycemia of T2DM is often treated with anti-diabetic drugs with or without subcutaneous insulin injections,neither of which mimic the physiological glycemic control seen in individuals with fully functional pancreas.A sought after goal for the treatment of T2DM has been to harness the regenerative potential of pancreaticβ-cells that might obviate a need for exogenous insulin injections.A new study towards attaining this aim was reported by Yi et al,who have characterized a liver-derived protein,named betatrophin,capable of inducing pancreaticβ-cell proliferation in *** a variety of in vitro and in vivo methods,Yi et al,have shown that betatrophin was expressed mainly in the liver and adipose tissue of *** expression of betatrophin in the liver led to dramatic increase in the pancreaticβ-cell mass and higher output of insulin in mice that also concomitantly elicited improved glucose *** authors discovered that betatrophin was also present in the human ***,betatrophin has been previously described by three other names,i.e.,re-feeding-induced fat and liver protein,lipasin and atypical angiopoeitin-like 8,by three independent laboratories,as nutritionally regulated liver-enriched factors that control serum triglyceride levels and lipid *** et al demonstration of betatrophin,as a circulating hormone that regulatesβ-cell proliferation,if successfully translated in the clinic,holds the potential to change the course of current therapies for diabetes.

关键词： Type 2 diabetes mellitus Insulin resistance Liver-derived betatrophin Pancreas β -cell regeneration

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Ménage-à-trois of bariatric surgery,bile acids and the gut microbiome

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World Journal of Diabetes 2015年第3期6卷 367-370页

作者： rajendra raghow Department of Veterans Affairs Medical Center Department of Pharmacology University of Tennessee Health Science Center

Bariatric surgeries have emerged as highly effective treatments for obesity associated type-2 diabetes ***,the desired therapeutic endpoints such as rates of weight loss,lower levels of glycated hemoglobin and remission of diabetes are achieved more rapidly and last longer following bariatric surgery,as opposed to drug therapies *** light of these findings,it has been suspected that in addition to causing weight loss dependent glucose intolerance,bariatric surgery induces other physiological changes that contribute to the alleviation of ***,the putative post-surgical neuro-hormonal pathways that underpin the therapeutic benefits of bariatric surgery remain *** a recent report,Ryan and colleagues shed new light on the potential mechanisms that determine the salutary effects of bariatric surgery in *** authors demonstrated that the improved glucose tolerance and weight loss in mice after vertical sleeve gastrectomy(VSG) surgery were likely to be caused by post-surgical changes in circulating bile acids and farnesoid-X receptor(FXR) signaling,both of which were also mechanistically linked to changes in the microbial ecology of the *** authors arrived at this conclusion from a comparison of genome-wide,metabolic consequences of VSG surgery in obese wild type(WT) and FXR knockout *** expression in the distal small intestines of WT and FXR knockout mice revealed that the pathways regulating bile acid composition,nutrient metabolism and anti-oxidant defense were differentially altered by VSG surgery in WT and FXR-/-*** on these data Ryan et al,hypothesized that bile acid homeostasis and FXR signaling were mechanistically linked to the gut microbiota that played a role in modulating post-surgical changes in total body mass and glucose *** authors' data provide a plausible explanation for putative weight loss-independent benefits of bariatric surgery and its relationship with metabolism of bile acids.

关键词： Vertical sleeve gastrectomy Bile acids Farnesoid-X-receptor Type-2 diabetes mellitus Gutmicrobiome Bariatric surgery

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Metabolic balancing acts of vitamin A in type-2 diabetes and obesity

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World Journal of Diabetes 2012年第10期3卷 174-177页

Using mice that lack retinaldehyde dehydrogenase 1 gene(Raldh1-/-mice),Kierfer et al demonstrated that retinoids(metabolites of Vitamin A) play an important role in the regulation of cellular metabolisms and *** Aldh1a1-/-mice were leaner and less prone to accumulate subcutaneous and visceral fat,and to acquire insulin resistance on high fat *** lower fasting glucose levels concomitant with reduced hepatic expression of glucose 6-phosphatase and phosphoenol pyruvate carboxy kinase genes indicated that Aldh1a1-/-mice were defective in *** mice also had lower plasma levels of triglycerides,very low-density lipoprotein and lowdensity lipoprotein-triacylglycerol,while their skeletal muscles elicited higher expression of carnitine palmatoyl transferase,medium chain acyl-A dehydrogenase,peroxisome proliferation activated receptor(PPARα and PPARδ.Thus,the improved lipid and lipoprotein profiles of Raldh1a1-/-mice resulted from a combination of reduced lipogenesis and enhanced fatty acid oxidation by *** mechanistic details of how retinoids integrate fasting glucose,hepatic gluconeogenesis and adaptive thermogenesis independent of body mass deserve further study.

关键词： Retinaldehyde dehydrogenase 1 Vitamin A Retinoids Gluconeogenesis type 2 diabetes

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Promoting rigor in blockchain energy and environmental footprint research:A systematic literature review

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Blockchain(Research and Applications) 2024年第1期5卷 133-151页

作者： Ashish rajendra Sai Harald Vranken Department of Computer Science Open UniversiteitHeerlen6419 ATthe Netherlands Department of Advanced Computing Sciences Maastricht UniversityMaastricht6211 LKthe Netherlands Institute for Computing&Information Sciences Radboud UniversityNijmegen6525 XZthe Netherlands

There is a growing interest in understanding the energy and environmental footprint of digital currencies,specifically in cryptocurrencies such as Bitcoin and *** cryptocurrencies are operated by a geographically distributed network of computing nodes,making it hard to estimate their energy consumption *** studies,both in academia and industry,attempt to model cryptocurrency energy consumption often based on a number of assumptions,for instance,about the hardware in use or the geographic distribution of the computing nodes.A number of these studies have already been widely criticized for their design choices and subsequent over-or under-estimation of energy *** this study,we evaluate the reliability of prior models and estimates by leveraging existing scientific literature from fields cognizant of blockchain,such as social energy sciences and information *** first design a quality assessment framework based on existing research,and we then conduct a systematic literature review examining scientific and non-academic literature demonstrating common issues and potential avenues of addressing these *** goal with this article is to advance the field by promoting scientific rigor in studies focusing on blockchain energy *** that end,we provide a novel set of codes of conduct for the five most widely used research methodologies:Quantitative energy modeling,literature reviews,data analysis and statistics,case studies,and *** envision that this code of conduct would assist in standardizing the design and assessment of studies focusing on blockchain-based systems’energy and environmental footprint.

关键词： Blockchain Energy consumption Environmental footprint Scientific rigor Reliability

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Foeniculum vulgare *** lipopolysaccharide-induced microglia activation and ameliorates neuroinflammation-mediated behavioral deficits in mice

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Asian Pacific Journal of Tropical Biomedicine 2024年第1期14卷 28-39页

作者： Sushruta Koppula Ramesh Alluri Spandana rajendra Kopalli College of Biomedical and Health Sciences Konkuk UniversityChungju-SiChungcheongbuk Do27478Republic of Korea Cognitive Science Research Initiative Lab Department of PharmacologyVishnu Institute of Pharmaceutical Education and ResearchNarsapurTelangana502313India Department of Bioscience and Biotechnology Sejong UniversityGwangjin-guSeoul 05006Republic of Korea

Objective:To investigate the effect of Foeniculum vulgare extract against lipopolysaccharide(LPS)-induced microglial activation in vitro as well as cognitive behavioral deficits in ***:LPS-activated BV-2 cell viability was measured using MTT assay and reactive oxygen species(ROS)was studied using DCF-DA *** antioxidative enzymes and pro-inflammatory mediators were analyzed using respective ELISA kits and Western *** in vivo testing,LPS(1 mg/kg,i.p.)was given daily for five days in male Swiss albino mice to produce chronic *** and behavioral tests were performed using open-field,passive avoidance,and rotarod experiments in LPS-induced ***:Foeniculum vulgare extract(25,50 and 100μg/mL)significantly attenuated the LPS-activated increase in nitric oxide(NO),ROS,cyclooxygenase-2,inducible NO synthase,IL-6,and TNF-alpha(P<0.05).Moreover,LPS-induced oxidative stress and reduced antioxidative enzyme levels were significantly improved by Foeniculum vulgare extract(P<0.05).The extract also regulated the NF-κB/MAPK signaling in BV-2 *** an in vivo study,Foeniculum vulgare extract(50,100,and 200 mg/kg)markedly mitigated the LPS-induced cognitive and locomotor impairments in *** fingerprinting analysis showed distinctive peaks with rutin,kaempferol-3-O-glucoside,and anethole as identifiable ***:Foeniculum vulgare extract can ameliorate LPS-stimulated neuroinflammatory responses in BV-2 microglial cells and improve cognitive and locomotor performance in LPS-administered mice.

关键词： Foeniculum vulgare Microglia Lipopolysaccharide Antioxidant Neuroinflammation MAPK signaling Cognition

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