scholarly journals Aging mitigates the severity of obesity-associated metabolic sequelae in a gender independent manner

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria E. Moreno-Fernandez ◽  
Vishakha Sharma ◽  
Traci E. Stankiewicz ◽  
Jarren R. Oates ◽  
Jessica R. Doll ◽  
...  
Keyword(s):  
Severe Obesity ◽  
Type I ◽  
Metabolic Dysfunction ◽  
Housing Conditions ◽  
Independent Manner ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Inflammatory Pathways ◽  
Feeding Regimen ◽  
The Impact

Abstract Background Understanding gender-associated bias in aging and obesity-driven metabolic derangements has been hindered by the inability to model severe obesity in female mice. Methods Here, using chow- or high fat diet (HFD)-feeding regimens at standard (TS) and thermoneutral (TN) housing temperatures, the latter to model obesity in female mice, we examined the impact of gender and aging on obesity-associated metabolic derangements and immune responsiveness. Analysis included quantification of: (i) weight gain and adiposity; (ii) the development and severity of glucose dysmetabolism and non-alcoholic fatty liver disease (NAFLD); and (iii) induction of inflammatory pathways related to metabolic dysfunction. Results We show that under chow diet feeding regimen, aging was accompanied by increased body weight and white adipose tissue (WAT) expansion in a gender independent manner. HFD feeding regimen in aged, compared to young, male mice at TS, resulted in attenuated glucose dysmetabolism and hepatic steatosis. However, under TS housing conditions only aged, but not young, HFD fed female mice developed obesity. At TN however, both young and aged HFD fed female mice developed severe obesity. Independent of gender or housing conditions, aging attenuated the severity of metabolic derangements in HFD-fed obese mice. Tempered severity of metabolic derangements in aged mice was associated with increased splenic frequency of regulatory T (Treg) cells, Type I regulatory (Tr1)-like cells and circulating IL-10 levels and decreased vigor of HFD-driven induction of inflammatory pathways in adipose and liver tissues. Conclusion Our findings suggest that aging-associated altered immunological profile and inflammatory vigor may play a dominant role in the attenuation of obesogenic diet-driven metabolic dysfunction.

scholarly journals Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Peter Dornbos ◽  
Amanda Jurgelewicz ◽  
Kelly A. Fader ◽  
Kurt Williams ◽  
Timothy R. Zacharewski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Cholesterol Homeostasis ◽  
Hepatic Glycogen ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Aryl Hydrocarbon ◽  
The Impact

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.

scholarly journals Clinical Validity of the diagnostic criteria for metabolic-associated fatty liver disease: a real-world experience

2020 ◽  
Author(s):  
Yasser Fouad ◽  
Zeinab Saad ◽  
Ehab Abdel Raheem ◽  
Yasser Abel gany ◽  
Hend Moness ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Multivariable Analysis ◽  
Metabolic Dysfunction ◽  
Alcoholic Fatty Liver ◽  
Clinical Criteria ◽  
Nafld Fibrosis Score ◽  
Definition Of ◽  
The Impact

Background and Aims: To eliminate the anti-definition of non-alcoholic fatty liver disease (NAFLD), positive clinical criteria for metabolic associated fatty liver disease are recently proposed. In this study, we examine the validation and utilization of these criteria. METHODS: Two cohorts of 316 consecutive patients were recruited, including 242 patients previously diagnosed to have NAFLD and 74 patients with concomitant NAFLD and chronic hepatitis C (CHC) The validity of the proposed criteria for MAFLD, namely presence of hepatic steatosis with one of three criteria, overweight/obesity, diabetes or evidence of metabolic dysregulation was assessed. Fibrosis was assessed using, fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS). The impact of MAFLD on the clinical outcomes in CHC patients was also investigated. Results: The clinical criteria captured 240 patients (99.2%). 215 (88.8%) met either overweight or diabetes and 25 (10.3%) met the presence of 2 criteria of metabolic dysfunction. In patients, with dual etiologies, in the multivariable analysis adjusting for age, sex, BMI, ALT, AST and diabetes, the presence of MAFLD were significantly associated with increase high FIB-4 score of fibrosis (Odds ratio [95% confidence interval], 3.77 [1.49-9.48], P < 0.005) when compared to those with MAFLD only. CONCLUSION: The proposed criteria for diagnosis of MAFLD is well validated and easily applicable to the entire spectrum of disease including non-obese subjects. Patients with lean MAFLD have favorable metabolic and fibrosis characteristics compared to their obese counterpart, while patients with concomitant MAFLD and CHC had severe metabolic and fibrosis characteristics compared to patients with MAFLD alone.

Rosiglitazone requires hepatocyte PPARγ expression to promote steatosis in male mice with diet-induced obesity

Endocrinology ◽  
2021 ◽  
Author(s):  
Samuel M Lee ◽  
Jose Muratalla ◽  
Alberto Diaz-Ruiz ◽  
Pablo Remon-Ruiz ◽  
Maximillian McCann ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Severe Obesity ◽  
Therapeutic Potential ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Short Term ◽  
Alcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Pparγ Expression ◽  
The Impact

Abstract Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ agonists that could reduce hepatic steatosis through their effects in adipose tissue, and therefore have been assessed as potential therapies to treat non-alcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a NAFLD therapy. To further explore this possibility, we examined the impact of short-term rosiglitazone maleate treatment after the development of moderate or severe diet-induced obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (Pparg △Hep) mice. Independent of the level of obesity and hepatic PPARγ expression, the TZD treatment enhanced insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic TG content, only in control mice with severe obesity. Under these conditions, Pparg △Hep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of adiponectin, while hepatic levels of phosphorylated AMP-activated protein kinase (AMPK) were also increased. In addition, in mice with severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the anti-steatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat NAFLD.

scholarly journals Long-term effects of western diet consumption in male and female mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu Hasegawa ◽  
Shin-Yu Chen ◽  
Lili Sheng ◽  
Prasant Kumar Jena ◽  
Karen M. Kalanetra ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Western Diet ◽  
Long Term Effects ◽  
Alcoholic Fatty Liver ◽  
Male And Female ◽  
Sexual Dimorphisms ◽  
Female Mice ◽  
Males And Females ◽  
The Impact

Abstract Long-term consumption of a diet with excessive fat and sucrose (Western diet, WD) leads to an elevated risk of obesity and metabolic syndrome in both males and females. However, there are sexual dimorphisms in metabolism which are apparent when considering the prevalence of complications of metabolic syndrome, such as non-alcoholic fatty liver disease. This study aimed to elucidate the impact of a WD on the metabolome and the gut microbiota of male and female mice at 5, 10, and 15 months to capture the dynamic and comprehensive changes brought about by diet at different stages of life. Here we show that there are important considerations of age and sex that should be considered when assessing the impact of diet on the gut microbiome and health.

scholarly journals GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner

2021 ◽  
Vol 248 (1) ◽  
pp. 31-44
Author(s):  
Andre Sarmento-Cabral ◽  
Mercedes del Rio-Moreno ◽  
Mari C Vazquez-Borrego ◽  
Mariyah Mahmood ◽  
Elena Gutierrez-Casado ◽  
...  
Keyword(s):  
Liver Injury ◽  
De Novo ◽  
Whole Body ◽  
Independent Manner ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Relative Contribution ◽  
Liver Gene ◽  
Induced Changes ◽  
The Impact

A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

The impact of a dedicated metabolic hepatology clinic for the treatment of non-alcoholic fatty liver disease

2017 ◽  
Author(s):  
Kenzo Motohashi ◽  
Ahmad Moolla ◽  
Tom Marjot ◽  
Mark Ainsworth ◽  
Jeremy Tomlinson ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

828-P: The Impact of Diabetes and Depression Status on Weight Loss Outcomes in Mexican Patients with Severe Obesity

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 828-P
Author(s):  
MARCELA RODRIGUEZ FLORES ◽  
SYLVANA STEPHANO Z. ◽  
MARÍA RABASA ◽  
JUANA MONTOYA ◽  
CLAUDIA VELEZ ◽  
...  
Keyword(s):  
Weight Loss ◽  
Severe Obesity ◽  
Depression Status ◽  
Weight Loss Outcomes ◽  
The Impact ◽  
Mexican Patients

Population Study on the Impact Food Chemical Composition on Patients with Non-Alcoholic Fatty Liver Diseases

2018 ◽  
Vol 69 (4) ◽  
pp. 961-964
Author(s):  
Andrei Vasile Olteanu ◽  
Georgiana Emmanuela Gilca Blanariu ◽  
Gheorghe Gh. Balan ◽  
Dana Elena Mitrica ◽  
Elena Gologan ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Fatty Liver ◽  
Nutritional Value ◽  
Liver Steatosis ◽  
Saturated Fat ◽  
Control Group ◽  
Healthy Population ◽  
Alcoholic Fatty Liver ◽  
Major Interest ◽  
The Impact

Non-alcoholic fatty liver disease (NAFLD) has become of major interest worldwide, it is estimated that more than 20% of the general population suffer from liver steatosis. NAFLD is highly associated with metabolic risk factors like type 2 diabetes mellitus, obesity and dyslipidemia, the patients diagnosed with NAFLD should adopt a high fiber low calorie diet, with reduced saturated fat and carbohydrates content, leading to weight loss and improvement of metabolic profile. Our study is aiming to shape the profile of the patient interested in being informed related to food quality and chemical composition and to evaluate the aspects on the food products label which are important for the customer. Between June 2017 and December 2017, 83 patients diagnosed with NASH were included in the study, representing the study group, while 33 subjects, without metabolic syndrome or digestive diseases, selected from patient list belonging to two general practitioners, constituted the control group. Related to the interest of being informed about the chemical composition and nutritional value of the products bought, the study showed a low interest for the provided information on nutritional value. lack of confidence in the provided information and complexity of the information are understandable, the high number of subject reasoning through lack of immediate clinical benefit is surprising. Among the healthy population the willingness to pay attention to this aspect is extremely low.

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