Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells

Objective

Patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) has been identified as a modifier of lipid metabolism. To better understand the physiological role of PNPLA3/adiponutrin, we have investigated its regulation in intact mice and human hepatocytes under various nutritional/metabolic conditions.

Material/methods

PNPLA3 gene expression was determined by real-time PCR in liver of C57BL/6 mice after dietary treatments and in HepG2 cells exposed to various nutritional/metabolic stimuli. Intracellular lipid content was determined in HepG2 cells after siRNA-mediated knockdown of PNPLA3.

Results

In vivo, mice fed a high-carbohydrate (HC) liquid diet had elevated hepatic lipid content, and PNPLA3 mRNA and protein expression, compared to chow-fed mice. Elevated expression was completely abrogated by addition of unsaturated lipid emulsion to the HC diet. By contrast, in mice with high-fat diet-induced steatosis, Pnpla3 expression did not differ compared to low-fat fed mice. In HepG2 cells, Pnpla3 expression was reversibly suppressed by glucose depletion and increased by glucose refeeding, but unchanged by addition of insulin and glucagon. Several unsaturated fatty acids each significantly decreased Pnpla3 mRNA, similar to lipid emulsion in vivo. However, Pnpla3 knockdown in HepG2 cells did not alter total lipid content in high glucose- or oleic acid-treated cells.

Conclusions

Our results provide evidence that PNPLA3 expression is an early signal/signature of carbohydrate-induced lipogenesis, but its expression is not associated with steatosis per se. Under lipogenic conditions due to high-carbohydrate feeding, certain unsaturated fatty acids can effectively suppress both lipogenesis and PNPLA3 expression, both in vivo and in a hepatocyte cell line.     

A very low carbohydrate ketogenic diet prevents the progression of hepatic steatosis caused by hyperglycemia in a juvenile obese mouse model

Objective:

To investigate whether the improvement in hyperglycemia by dietary control influences hyperglycemia-induced pathologies in tissues of juvenile obese (ob/ob) mice.

Design:

Five-week-old ob/ob mice were fed a very low carbohydrate ketogenic diet (KD) for 7 weeks. The blood glucose levels and body weight were monitored during this period. Biochemical parameters in the serum and tissue pathologies of the mice were analyzed at the end of the 7-week period.

Results:

The hyperglycemic phenotype of the ob/ob mice was improved by KD feeding for 7 weeks. Surprisingly, we found that KD feeding also drastically reduced the hepatic steatosis phenotype in ob/ob mice, while their obesity phenotype was unaltered. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that several proteins found in the liver of ob/ob mice fed a regular chow diet were undetectable after being fed KD. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) MASCOT search and western blot analysis revealed that the proteins absent from the mice fed KD included fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), which are key enzymes for lipogenesis in the liver. Fatty acid analysis supported the results because the ratio of C18:1, which is a major product of lipogenesis, was reduced by KD feeding. However, C18:2, which cannot be synthesized in mammalian cells but is present in the KD, was found to be a major component in the liver of KD-fed ob/ob mice.

Conclusion:

Hyperglycemia promotes hepatic steatosis via the lipogenic pathway in the liver of juvenile ob/ob mice. However, the development of steatosis is prevented by feeding KD owing to an improvement in hyperglycemia. We found that the progression of steatosis is reflected by the composition of fatty acids in the total lipids of the liver and serum.     

The one year exercise and lifestyle intervention program KLAKS: Effects on anthropometric parameters,cardiometabolic risk factors and glycemic control in childhood obesity

Objective

Regular physical exercise within structured lifestyle programs may improve weight status and minimize metabolic risk factors in childhood obesity. The aim of this study was to evaluate the effect of the one-year combined physical exercise/lifestyle program KLAKS on anthropometric and metabolic parameters and glycemic control in childhood obesity.

Materials and Methods

142 overweight/obese (BMI > 90th percentile) candidates (7–18 years) were enrolled, 115 participants completed the program. Anthropometrics and biochemical parameters were obtained at beginning and completion. An oral glucose tolerance test (OGTT) was performed in a subgroup of participants. Course of glucose and insulin levels within OGTT was correlated with several parameters and is reported here for those who completed the program.

Results

The mean standard deviation scores (SDS) decreased significantly for BMI, waist circumference, waist-to-height ratio (WHtR) and percentage body fat (all p ≤ 0.01). Improved metabolic risk markers included mean glucose levels within an OGTT at follow-up compared to baseline (p < 0.0001) and HbA1c (p = 0.05) as well as indications of improvement for gamma-glutamyl-transferase and free fatty acids.

Conclusions

The one-year combined exercise/lifestyle program KLAKS significantly improves markers of obesity and glycemic control. Impaired cardiometabolic risk markers, even subclinical, are also favorably influenced by program participation.     

Estrogen receptor α is not a candidate gene for metabolic syndrome in Caucasian elderly subjects

Objective

Variants of estrogen receptor α (ERα) have been associated with obesity, dyslipidemia, diabetes and blood pressure. The Middle East registers some of the highest rate of metabolic syndrome worldwide. The aim of this study is to investigate the relationship between metabolic syndrome, a clustered combination of these metabolic factors, and polymorphisms PvuII and XbaI of ERα in Lebanese Caucasian elderly overweight subjects.

Material/Methods

250 Caucasian Lebanese unrelated elderly men and women, median age 71 years, were studied. ERα intronic polymorphisms variants, PvuII and XbaI diplotypes and genotypes, were examined. Associations with metabolic syndrome, defined by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), and its components, namely high density lipoprotein (HDL), fasting glucose levels, blood pressure, and waist circumference were evaluated in regression models.

Results

ER α diplotypes and genotypes distributions were similar between participants with and without metabolic syndrome, in the overall group of subjects, and by gender. No consistent associations between the diplotypes and genotypes tested and metabolic syndrome, or its components, could be detected.

Conclusions

Genetic variants in ERα were not associated with metabolic syndrome or its components, in a group of 250 Lebanese Caucasian elderly participants, a group with a high prevalence of metabolic syndrome.     

Artemisia scoparia extract attenuates non-alcoholic fatty liver disease in diet-induced obesity mice by enhancing hepatic insulin and AMPK signaling independently of FGF21 pathway

Objective

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease which has no standard treatment. In this regard, we sought to evaluate the effects of extracts of Artemisia santolinaefolia (SANT) and Artemisia scoparia (SCO) on hepatic lipid deposition and cellular signaling in a diet-induced obesity (DIO) animal model.

Materials/Methods

DIO C57/B6J mice were randomly divided into three groups, i.e. HFD, SANT and SCO. Both extracts were incorporated into HFD at a concentration of 0.5% (w/w). Fasting plasma glucose, insulin, adiponectin, and FGF21 concentrations were measured.

Results

At the end of the 4-week intervention, liver tissues were collected for analysis of insulin, AMPK, and FGF21 signaling. SANT and SCO supplementation significantly increased plasma adiponectin levels when compared with the HFD mice (P < 0.001). Fasting insulin levels were significantly lower in the SCO than HFD mice, but not in SANT group. Hepatic H&E staining showed fewer lipid droplets in the SCO group than in the other two groups. Cellular signaling data demonstrated that SCO significantly increased liver IRS-2 content, phosphorylation of IRS-1, IR β, Akt1 and Akt2, AMPK α1 and AMPK activity and significantly reduced PTP 1B abundance when compared with the HFD group. SCO also significantly decreased fatty acid synthase (FAS), HMG-CoA Reductase (HMGR), and Sterol regulatory element-binding protein 1c (SREBP1c), but not Carnitine palmitoyltransferase I (CPT-1) when compared with HFD group. Neither SANT nor SCO significantly altered plasma FGF21 concentrations and liver FGF21 signaling.

Conclusion

This study suggests that SCO may attenuate liver lipid accumulation in DIO mice. Contributing mechanisms were postulated to include promotion of adiponectin expression, inhibition of hepatic lipogenesis, and/or enhanced insulin and AMPK signaling independent of FGF21 pathway.     

Bone metabolism in obese rats programmed by early weaning

Objective

Obesity and osteoporosis seem to have a common pathogenesis, especially because bone and adipose tissue have common origins. Since early weaning (EW) decreases adipogenesis and osteogenesis in neonate, further programming for obesity and hyperleptinemia, we hypothesized that these changes in adipogenesis could affect bone metabolism.

Materials/Methods

Lactating rats were separated into 3 groups: control — dams whose pups ate milk throughout lactation; mechanical EW (MEW) — dams were involved with a bandage interrupting suckling in the last 3 days of lactation; pharmacological EW (PEW) — dams were bromocriptine-treated (0.5 mg/twice a day via intraperitoneal injection) 3 days before weaning. The adult offspring was subjected to dual-energy X-ray absorptiometry and bone tissue was also evaluated by computed tomography, microcomputed tomography and biomechanical tests, beyond serum analyses.

Results

MEW and PEW presented higher total bone mineral density (BMD), total bone mineral content, spine BMD and bone area in postnatal day 150 (PN150). In PN180, both groups also presented increase of these parameters and higher femur BMD and fourth lumbar vertebra (LV4) BMD, femoral head radiodensity and LV4 vertebral body radiodensity, trabecular number, stiffness and break load; lower trabecular separation, maximal deformation and break deformation, and also hyperleptinemia and higher visceral fat mass and 25-hydroxivitamin D, whereas parathyroid hormone was unchanged. Serum C-terminal cross-linked telopeptide of type I collagen was lower for both groups.

Conclusions

Since both models program for obesity and increased bone mass, and leptin increases plasma vitamin D levels, probably leptin is the link between obesity and higher bone mass.     

Superantigen activates the gp130 receptor on adipocytes resulting in altered adipocyte metabolism

Objective

The bacteria Staphylococcus aureus is part of the normal bacterial flora and produces a repertoire of enterotoxins which can cause food poisoning and toxic shock and might contribute to the pathogenesis of inflammatory diseases. These enterotoxins directly cross-link the T cell receptor with MHC class II, activating large amounts of T cells and are therefore called superantigens. It was recently discovered that the superantigen SEA binds to the cytokine receptor gp130. As obesity and type 2 diabetes are highly associated with inflammation of the adipose tissue and gp130 has been shown to play an important role in adipocytes, we wanted to investigate the effect of SEA on adipocyte signaling and function.

Materials/methods

Binding of SEA to gp130 was examined using surface plasmon resonance in a cell free system. Effects of SEA on adipocyte signaling, insulin sensitivity and function were studied using western blotting and biological assays for lipolysis, lipogenesis and glucose uptake.

Results

We demonstrate that SEA binds to gp130 with a medium affinity. Furthermore, SEA induces phosphorylation of a key downstream target, STAT3, in adipocytes. SEA also inhibits insulin-induced activation of PKB and PKB downstream signaling which was associated with reduced basal and insulin induced glucose uptake, reduced lipogenesis as well as reduced ability of insulin to inhibit lipolysis.

Conclusions

SEA inhibits insulin signaling as well as insulin biological responses in adipocytes supporting that bacterial infection might contribute to the development of insulin resistance and type 2 diabetes.     

Bariatric surgery in severely obese adolescents improves major comorbidities including hyperuricemia

Objective

Serum uric acid (sUA) is believed to contribute to the pathogenesis of metabolic comorbidities like hypertension, insulin-resistance (IR) and endothelial dysfunction (EDF) in obese children. The present pilot study investigated the association between sUA concentrations and loss of body weight following laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y-gastric bypass (RYGB) in severely obese adolescents.

Materials/Methods

10 severely obese adolescents underwent either LSG (n = 5) or RYGB (n = 5). 17 normal weight, healthy, age- and gender-matched adolescents served as a normal weight peer group (NWPG). Pre- and 12 months postoperatively, sUA and relevant metabolic parameters (glucose homeostasis, transaminases, lipids) were compared.

Results

Preoperatively, sUA was significantly elevated in patients with severe obesity compared to NWPG. Twelve months after LSG and RYGB, a significant decrease in sUA, BMI, CVD risk factors, hepatic transaminases, and HOMA-IR was observed. Reduction in SDS-BMI significantly correlated with changes in sUA.

Conclusions

sUA levels and metabolic comorbidities improved following bariatric surgery in severely obese adolescents. The impact of changes in sUA on long-term clinical complications of childhood obesity deserves further study.     

Adult Living Donor Liver Transplantation Using Hepatitis B Core Antibody-Positive Grafts in Korea, a Hepatitis B-endemic Region

Background/Aims

The exclusion of hepatitis B core antibody (HBcAb)-positive donors from liver transplants (LTs) due to the risk of transmitting hepatitis B virus (HBV) does not appear to be practical in Korea, where hepatitis B is endemic. This study assessed the risk of de novo HBV infection in hepatitis B surface antigen (HBsAg)-negative LT recipients receiving a liver from HBcAb-positive donors.

Methods

Of 341 adult living donor LTs conducted at our institution between March 2001 and September 2008, 176 donors (51.6%) were HBcAb-positive, and 26 HBcAb-positive grafts were transplanted to HBsAg-negative recipients. The median follow-up time after LT was 41.9 months.

Results

Without anti-HBV prophylaxis, 2 out of 26 (7.7%) HBsAg-negative recipients who received grafts from HBcAb-positive donors developed de novo HBV infection 20 and 85 months after LT. These patients had been negative for all HBV serologic markers before transplantation. In both cases, there were no abnormalities in liver function tests upon diagnosis of de novo HBV infection.

Conclusions

De novo HBV infection from HBcAb-positive donors after LT does not appear to be of great concern in terms of the number of cases in Korea because high risk patients who are HBV-negative comprise only a small proportion of the recipients. However, HBV-naïve LT recipients still carry the risk of developing de novo HBV infection as in non-HBV endemic areas.     

Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a Mouse model of Western diet induced obesity

Objective

Consumption of a high-fat/high-fructose Western diet (WD) is linked to rising obesity and heart disease, particularly diastolic dysfunction which characterizes early obesity/metabolic cardiomyopathy. Mounting evidence supports a role for inflammation, oxidative stress and fibrosis in the pathophysiology of metabolic cardiomyopathy. Dipeptidyl peptidase-4 (DPP-4) is a circulating exopeptidase recently reported to be elevated in the plasma of patients with insulin resistance (IR), obesity and heart failure. We hypothesized that a model of WD induced obesity/metabolic cardiomyopathy would exhibit increased DPP-4 activity and cardiac fibrosis with DPP-4 inhibition preventing cardiac fibrosis and the associated diastolic dysfunction.

Materials/Methods

Four-week-old C57BL6/J mice were fed a high-fat/high-fructose WD with the DPP-4 inhibitor MK0626 for 16 weeks. Cardiac function was examined by high-resolution cine-cardiac magnetic resonance imaging (MRI). Phenotypic analysis included measurements of body and heart weight, systemic IR and DPP-4 activity. Immunohistochemistry and transmission electron microscopy (TEM) were utilized to identify underlying pathologic mechanisms.

Results

We found that chronic WD consumption caused obesity, IR, elevated plasma DPP-4 activity, heart enlargement and diastolic dysfunction. DPP-4 inhibition with MK0626 in WD fed mice resulted in > 75% reduction in plasma DPP-4 activity, improved IR and normalized diastolic relaxation. WD consumption induced myocardial oxidant stress and fibrosis with amelioration by MK0626. TEM of hearts from WD fed mice revealed abnormal mitochondrial and perivascular ultrastructure partially corrected by MK0626.

Conclusions

This study provides evidence of a role for increased DPP-4 activity in metabolic cardiomyopathy and a potential role for DPP-4 inhibition in prevention and/or correction of oxidant stress/fibrosis and associated diastolic dysfunction.     

Dietary lipid-dependent regulation of de novo lipogenesis and lipid partitioning by ketogenic essential amino acids in mice

Background:

We have previously reported that dietary ketogenic amino acids (KAAs) modulate hepatic de novo lipogenesis (DNL) and prevent hepatic steatosis in mice. However, the dependence of the metabolic phenotypes generated by KAA on the type of dietary lipid source remains unclear.

Objective:

The aim of this study was to assess the effect of KAA combined with different dietary lipid sources on hepatic DNL and tissue lipid partitioning in mice.

Design:

We compared three different KAA-supplemented diets, in which a portion of the dietary protein was replaced by five major essential amino acids (Leu, Ile, Val, Lys and Thr) in high-fat diets based on palm oil (PO), high-oleic safflower oil (FO) or soy oil (SO). To compare the effects of these diets in C57B6 mice, the differential regulation of DNL and dietary lipid partitioning due to KAA was assessed using stable isotopic flux analysis.

Results:

The different dietary oils showed strikingly different patterns of lipid partitioning and accumulation in tissues. High-PO diets increased both hepatic and adipose triglycerides (TG), whereas high-FO and high-SO diets increased hepatic and adipose TG, respectively. Stable isotopic flux analysis revealed high rates of hepatic DNL in high-PO and high-FO diets, whereas it was reduced in the high-SO diet. KAA supplementation in high-PO and high-FO diets reduced hepatic TG by reducing the DNL of palmitate and the accumulation of dietary oleate. However, KAA supplementation in the high-SO diet failed to reduce hepatic DNL and TG. Interestingly, KAA reduced SO-induced accumulation of hepatic linoleate and enhanced SO-induced accumulation of dietary oleate.

Conclusions:

Overall, the reduction of hepatic TG by KAA is dependent on dietary lipid sources and occurs through the modulation of DNL and altered partitioning of dietary lipids. The current results provide further insight into the underlying mechanisms of hepatic lipid reduction by amino acids.     

A new risk score predicting 1- and 5-year mortality following acute myocardial infarction Soroka Acute Myocardial Infarction (SAMI) Project

Background

Risk stratification of patients following acute myocardial infarction (AMI), in order to identify patients whose clinical outcomes can be improved through specific medical interventions, is needed.

Objectives

Development and validation of a prognostic tool comprising a variety of non-cardiovascular co-morbidities, to predict mortality of hospital survivors after AMI.

Methods

The study cohort included 2773 consecutive patients with AMI who were discharged live from the Soroka University Medical Center between 2002 and 2004. Two-thirds were used obtain the model (training set) and one-third to validate it (validation set). Data were collected from the hospital's routine computerized information systems. The primary outcome was post-discharge 1-year all-cause mortality. The weight of each variable in the final score was computed based on the odds ratio values of the multivariate model. Additionally, the ability of the index to predict 5-year mortality was assessed.

Results

These are comprised of the following parameters: 4 points — age > 75 years, abnormal echocardiography findings; 3 points — at least one of following: gastro-intestinal hemorrhage, COPD, malignancy, alcohol or drug addiction, neurological disorders, psychiatric disorders; 2 points — no echocardiography results, renal diseases, anemia, hyponatremia; −3 points for PCI or thrombolytic therapy; −6 points — CABG; −2 points — obesity. The c-statistics for 1-year all-cause mortality were 0.86 and 0.83 in the training and validation sets, respectively. The c-statistics for 5-year mortality was 0.858 for both sets combined.

Conclusions

The new score is a simple robust tool for predicting mortality in patients discharged alive following AMI.     

Effects of a nonnutritive sweetener on body adiposity and energy metabolism in mice with diet-induced obesity

Objective

Nonnutritive sweeteners (NNSs) have been studied in terms of their potential roles in type 2 diabetes, obesity, and related metabolic disorders. Several studies have suggested that NNSs have several specific effects on metabolism such as reduced postprandial hyperglycemia and insulin resistance. However, the detailed effects of NNSs on body adiposity and energy metabolism have not been fully elucidated. We investigated the effects of an NNS on energy metabolism in mice with diet-induced obesity (DIO).

Methods

DIO mice were divided into NNS-administered (4% NNS in drinking water), sucrose-administered (33% sucrose in drinking water), and control (normal water) groups. After supplementation for 4 weeks, metabolic parameters, including uncoupling protein (UCP) levels and energy expenditure, were assessed.

Results

Sucrose supplementation increased hyperglycemia, body adiposity, and body weight compared to the NNS-administered and control groups (P < 0.05 for each). In addition, NNS supplementation decreased hyperglycemia compared to the sucrose-administered group (P < 0.05). Interestingly, NNS supplementation increased body adiposity, which was accompanied by hyperinsulinemia, compared to controls (P < 0.05 for each). NNS also increased leptin levels in white adipose tissue and triglyceride levels in tissues compared to controls (P < 0.05 for each). Notably, compared to controls, NNS supplementation decreased the UCP1 level in brown adipose tissue and decreased O₂ consumption in the dark phase.

Conclusions

NNSs may be good sugar substitutes for people with hyperglycemia, but appear to influence energy metabolism in DIO mice.     

Prevalencia de obesidad infantil y juvenil en España en 2012

Introduction and objectives

Obesity is a major cardiovascular risk factor. In Spain, few studies have physically measured height and weight to estimate the magnitude of the problem. The aim of this study was to determine the prevalence of child and adolescent obesity in Spain in 2012.

Methods

We performed a cross-sectional probability sample of 1018 children, representative of the Spanish population aged between 8 and 17 years old, with objectively measured height and weight, along with other sociodemographic variables. We calculated the prevalence of overweight and obesity according to the criteria of the World Health Organization, the International Obesity Task Force, and the enKid study.

Results

In the group aged 8 to 17 years old, the prevalence of overweight and obesity was 26% and 12.6%, respectively; 4 in 10 young people were overweight or obese. Excess weight was found in 45% of the group aged 8 to 13 years and in 25.5% of that aged 14 to 17 years. This cardiovascular risk factor was associated with lower social class and lower educational level.

Conclusions

The prevalence of overweight and obesity in children and adolescents in Spain remains high (close to 40%), but has not increased in the last 12 years.Full English text available from:www.revespcardiol.org/en.     

La grasa epicárdica se relaciona con la visceral,el síndrome metabólico y la resistencia a la insulina en mujeres menopáusicas

Introduction and objectives

Epicardial adipose tissue has been associated with several obesity-related parameters and with insulin resistance. Echocardiographic assessment of this tissue is an easy and reliable marker of cardiometabolic risk. However, there are insufficient studies on the relationship between epicardial fat and insulin resistance during the postmenopausal period, when cardiovascular risk increases in women. The objective of this study was to examine the association between epicardial adipose tissue and visceral adipose tissue, waist circumference, body mass index, and insulin resistance in postmenopausal women.

Methods

A cross sectional study was conducted in 34 postmenopausal women with and without metabolic syndrome. All participants underwent a transthoracic echocardiogram and body composition analysis.

Results

A positive correlation was observed between epicardial fat and visceral adipose tissue, body mass index, and waist circumference. The values of these correlations of epicardial fat thickness overlying the aorta-right ventricle were r = 0.505 (P < .003), r = 0.545 (P < .001), and r = 0.515 (P < .003), respectively. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome than in those without this syndrome (mean [standard deviation], 544.2 [122.9] vs 363.6 [162.3] mm ²; P = .03).

Conclusions

Epicardial fat thickness measured by echocardiography was associated with visceral adipose tissue and other obesity parameters. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome. Therefore, echocardiographic assessment of epicardial fat may be a simple and reliable marker of cardiovascular risk in postmenopausal women.Full English text available from:www.revespcardiol.org/en     

Palmitate-induced Activation of Mitochondrial Metabolism Promotes Oxidative Stress and Apoptosis in H4IIEC3 Rat Hepatocytes

Objective

Hepatic lipotoxicity is characterized by reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and excessive apoptosis, but the precise sequence of biochemical events leading to oxidative damage and cell death remains unclear. The goal of this study was to delineate the role of mitochondrial metabolism in mediating hepatocyte lipotoxicity.

Materials/Methods

We treated H4IIEC3 rat hepatoma cells with free fatty acids in combination with antioxidants and mitochondrial inhibitors designed to block key events in the progression toward apoptosis. We then applied ¹³C metabolic flux analysis (MFA) to quantify mitochondrial pathway alterations associated with these treatments.

Results

Treatment with palmitate alone led to a doubling in oxygen uptake rate and in most mitochondrial fluxes. Supplementing culture media with the antioxidant N-acetyl-cysteine (NAC) reduced ROS accumulation and caspase activation and partially restored cell viability. However, ¹³C MFA revealed that treatment with NAC did not normalize palmitate-induced metabolic alterations, indicating that neither elevated ROS nor downstream apoptotic events contributed to mitochondrial activation. To directly limit mitochondrial metabolism, the complex I inhibitor phenformin was added to cells treated with palmitate. Phenformin addition eliminated abnormal ROS accumulation, prevented the appearance of apoptotic markers, and normalized mitochondrial carbon flow. Further studies revealed that glutamine provided the primary fuel for elevated mitochondrial metabolism in the presence of palmitate, rather than fatty acid beta-oxidation, and that glutamine consumption could be reduced through co-treatment with phenformin but not NAC.

Conclusion

Our results indicate that ROS accumulation in palmitate-treated H4IIEC3 cells occurs downstream of altered mitochondrial oxidative metabolism, which is independent of beta-oxidation and precedes apoptosis initiation.     

LCT-13910C > T polymorphism-associated lactose malabsorption and risk for colorectal cancer in Italy

Background

The activity of epithelial lactase (LCT) associates with a polymorphism 13910 bp upstream the LCT-encoding gene (LCT-13910C > T). The relationship between LCT-13910C > T polymorphism and risk for colorectal cancer is unclear.

Aims

We examined the relationship between the LCT-13910C > T polymorphism causing lactose intolerance and risk for colorectal cancer/polyps onset in the Italian population.

Patients and methods

793 subjects (306 with colorectal cancer, 176 with polyps and 311 controls) were genotyped for the LCT-13910C > T variant by TaqMan real time-PCR.

Results

Lactose malabsorption linked to the CC genotype did not associate with an increased risk for either colorectal cancer (OR = 1.041; 95% CI = 0.751–1.442; p = 0.868) or polyps (OR = 0.927; 95% CI = 0.630–1.363; p = 0.769). There was no association with colorectal cancer/polyps site. 60% of the subjects overall bore the CC genotype.

Conclusion

In the Italian population the LCT-13910C > T polymorphism is not associated to the risk for colorectal cancer or polyps.     

Detailed assessments of childhood adversity enhance prediction of central obesity independent of gender,race, adult psychosocial risk and health behaviors

Objective

This study examined whether a novel indicator of overall childhood adversity, incorporating number of adversities, severity, and chronicity, predicted central obesity beyond contributions of “modifiable” risk factors including psychosocial characteristics and health behaviors in a diverse sample of midlife adults. The study also examined whether the overall adversity score (number of adversities × severity × chronicity) better predicted obesity compared to cumulative adversity (number of adversities), a more traditional assessment of childhood adversity.

Materials/Methods

210 Black/African Americans and White/European Americans, mean age = 45.8; ± 3.3 years, were studied cross-sectionally. Regression analysis examined overall childhood adversity as a direct, non-modifiable risk factor for central obesity (waist–hip ratio) and body mass index (BMI), with and without adjustment for established adult psychosocial risk factors (education, employment, social functioning) and heath behavior risk factors (smoking, drinking, diet, exercise).

Results

Overall childhood adversity was an independent significant predictor of central obesity, and the relations between psychosocial and health risk factors and central obesity were not significant when overall adversity was in the model. Overall adversity was not a statistically significant predictor of BMI.

Conclusions

Overall childhood adversity, incorporating severity and chronicity and cumulative scores, predicts central obesity beyond more contemporaneous risk factors often considered modifiable. This is consistent with early dysregulation of metabolic functioning. Findings can inform practitioners interested in the impact of childhood adversity and personalizing treatment approaches of obesity within high-risk populations. Prevention/intervention research is necessary to discover and address the underlying causes and impact of childhood adversity on metabolic functioning.     

The obesity paradox in men with coronary heart disease and heart failure: The role of muscle mass and leptin

Aims

We have investigated the role of muscle mass, natriuretic peptides and adipokines in explaining the obesity paradox.

Background

The obesity paradox relates to the association between obesity and increased survival in patients with coronary heart disease (CHD) or heart failure (HF).

Methods

Prospective study of 4046 men aged 60–79 years followed up for a mean period of 11 years, during which 1340 deaths occurred. The men were divided according to the presence of doctor diagnosed CHD and HF: (i) no CHD or HF ii), with CHD (no HF) and (iii) with HF.

Results

Overweight (BMI 25–9.9 kg/m²) and obesity (BMI ≥ 30 kg/m²) were associated with lower mortality risk compared to men with normal weight (BMI 18.5–24.9 kg/m²) in those with CHD [hazards ratio (HR) 0.71 (0.56,0.91) and 0.77 (0.57,1.04); p = 0.04 for trend] and in those with HF [HR 0.57 (0.28,1.16) and 0.41 (0.16,1.09; p = 0.04 for trend). Adjustment for muscle mass and NT-proBNP attenuated the inverse association in those with CHD (no HF) [HR 0.78 (0.61,1.01) and 0.96 (0.68,1.36) p = 0.60 for trend) but made minor differences to those with HF [p = 0.05]. Leptin related positively to mortality in men without HF but inversely to mortality in those with HF; adjustment for leptin abolished the BMI mortality association in men with HF [HR 0.82 (0.31,2.20) and 0.99 (0.27,3.71); p = 0.98 for trend].

Conclusion

The lower mortality risk associated with excess weight in men with CHD without HF may be due to higher muscle mass. In men with HF, leptin (possibly reflecting cachexia) explain the inverse association.