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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Multiple lines of evidence from rodents have established a role for epigenetic remodeling in regulating gene transcription in response to an altered gestational milieu. However, to date, it is unknown whether variations in the intrauterine environment in primates similarly induce changes in key determinants of hepatic chromatin structure. We hypothesized that a maternal high-fat diet would alter the epigenomic profile of the developing offspring, which would result in alterations in fetal gene expression. Age- and weight-matched adult female Japanese macaques were placed on control (13% fat) or high-fat (35% fat) breeder diets and mated annually over a 4-year interval. Fetuses in successive years were delivered near term (e130 of 167 days) and underwent necropsy with tissue harvest. Fetal histones were acid extracted for characterization of H3 modification and chromatin immunoprecipitation (ChIP) with differential display PCR; fetal RNA, DNA, and cytoplasmic and nuclear protein extracts were similarly extracted for comparison. Chronic consumption of a maternal high-fat diet results in a threefold increase in fetal liver triglycerides and histologic correlates of non-alcoholic fatty liver disease. These gross changes in the fetal liver are accompanied by a statistically significant hyperacetylation of fetal hepatic tissue at H3K14 (199.85+/-9.64 vs 88.8+/-45.4; P=0.038) with a trend towards the increased acetylation at H3K9 (140.9+/-38.7 vs 46.6+/-6.53; P=0.097) and at H3K18 (69.0+/-3.54 vs 58.0+/-4.04; P=0.096). However, epigenetic modifications on fetal hepatic H3 associated with gene repression were absent or subtle (P>0.05). Subsequent characterization of key epigenetic determinants associated with H3 acetylation marks revealed similar significant alterations in association with a high-fat maternal diet (e.g., relative fetal histone deacetylase 1 (HDAC1) gene expression 0.61+/-0.25; P=0.011). Consistent with our mRNA expression profile, fetal nuclear extracts from offspring of high-fat diet animals were observed to be significantly relatively deplete of HDAC1 protein (36.07+/-6.73 vs 83.18+/-7.51; P=0.006) and in vitro HDAC functional activity (0.252+/-0.03 vs 0.698+/-0.02; P<0.001). We employ these observations in ChIP differential display PCR to attempt to identify potential fetal genes whose expression is reprogramed under conditions of a high-fat maternal diet. We quantitatively confirm a minimum of a 40% alteration in the expression of several genes of interest: glutamic pyruvate transaminase (alanine aminotransferase) 2 (GPT2) (1.59+/-0.23-fold; P=0.08), DNAJA2 (1.36+/-0.21; P=0.09), and Rdh12 (1.88+/-0.15; P=0.01) are appreciably increased in fetal hepatic tissue from maternal caloric-dense diet animals when compared with control while Npas2, a peripheral circadian regulator, was significantly downmodulated in the offspring of high-fat diet animals (0.66+/-0.08; P=0.03). In this study, we show that a current significant in utero exposure (caloric-dense high-fat maternal diet) induces site-specific alterations in fetal hepatic H3 acetylation. Employing ChIP, we extend these observations to link modifications of H3 acetylation with alterations in gene-specific expression. These results suggest that a caloric-dense maternal diet leading to obesity epigenetically alters fetal chromatin structure in primates via covalent modifications of histones and hence lends a molecular basis to the fetal origins of adult disease hypothesis.
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PMID:Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. 1851 2

Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease.
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PMID:Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. 1852 76

Non-alcoholic fatty liver disease is present in 15-25% of the general population. The fundamental derangement in non-alcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, dyslipidemia, hypertension, and obesity. The natural history of non-alcoholic fatty liver disease is not always benign, and causality for chronic liver disease and cirrhosis is well known in clinical practice and sometimes it is accompanied by hepatocellular carcinoma. Non-alcoholic fatty liver disease is likely to be associated with increased cardiovascular disease risk, and it raises the possibility that non-alcoholic fatty liver disease may be not only a marker but also an early mediator of atherosclerosis. Therapy is currently directed at treating components of the metabolic syndrome which may be beneficial also for the liver.
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PMID:[Non-alcoholic fatty liver disease and cardiovascular risk]. 1861 57

The global increase in the prevalence of obesity has heralded a rise in associated liver injury namely NAFLD (non-alcoholic fatty liver disease). It is estimated that 20-30% of adult populations in developed countries have NAFLD and, although high quality data is currently lacking, the condition is clearly increasing in children also. NAFLD should be suspected in those with commonly available simple clinical signs and biochemistry consistent with insulin resistance. A small number of individuals with NAFLD, often considered a relatively benign condition, will progress to more severe stages of liver disease including NASH (non-alcoholic steatohepatitis) with or without fibrosis, cirrhosis and occasionally hepatocellular carcinoma. NAFLD is also commonly associated with an increased risk of developing Type 2 diabetes and treatable features of insulin resistance such as dyslipidaemia and dysglycaemia. Histological examination of liver tissue remains the only proven method to distinguish between simple steatosis and NASH, a condition far more likely to progress to cirrhosis. Identification of an imaging technique or non-invasive marker to achieve this distinction is therefore much sought after and would allow larger clinical trials and better clinical assessment. Case series and pilot studies of lifestyle advice, insulin sensitizers and other medications have shown improvements in liver histology and serum liver enzymes but robust randomized controlled studies are needed. Furthermore, the cost/benefit ratio of any new therapies, and any potential harms, must be evaluated carefully before being clinically advocated.
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PMID:Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. 1866 68

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal approximately 4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.
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PMID:High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. 1875 70

Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, atherosclerosis, and non-alcoholic fatty liver disease. The evidence that obesity can be regarded as an inflammatory disease comes from numerous studies showing a moderate increase of circulating inflammatory factors in obese patients and the identification of different types of immune cells infiltrating the human adipose tissue. Obesity may induce a pro-inflammatory state, which can cause or worsen insulin resistance in adipose tissue, skeletal muscle, and liver. The causative factors of this inflammation process in obesity are not entirely understood, but adipose tissue seems to play an important role in the relationship between obesity and chronic inflammation. Increased infiltration of adipose tissue with immune cells could cause adipose tissue insulin resistance via autocrine and paracrine cytokine/adipokine signalling, which contributes to systemically decreased insulin sensitivity via endocrine signalling. On the other hand, obesity-induced inflammation could represent a compensatory mechanism for increased adipose tissue turnover in obese states, which might protect obese individuals against deleterious effects of fat accumulation. A better understanding of the mechanisms and molecular components of obesity induced inflammatory response might lead to identifying novel therapeutic targets to prevent obesity-related complications.
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PMID:The inflammatory process of adipose tissue. 1880 22

Fatty liver is one of the local morphological manifestations of metabolic syndrome and is frequently associated with insulin resistance. Insulin resistance is also common in patients with chronic hepatitis C. Hyperinsulinemia is an independent risk factor for hypertension and cardiovascular mortality. The aim of this study was to evaluate the therapeutic efficacy of angiotensin II receptor blockers (ARBs), telmisartan and olmesartan, for patients with non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CH-C). We analyzed the incidence of obesity, insulin resistance, and other disorders in patients with NAFLD (Group A), CH-C (Group B), or other liver diseases (Group C). We evaluated whether the ARBs, telmisartan and olmesartan, improved insulin resistance and liver injury by measuring the homeostasis model assessment ratio of insulin resistance (HOMA-IR) and serum alanine aminotransferase (ALT). The incidence of obesity (BMI > or =25 kg/m2) was significantly higher in Group A than in Groups B and C. The incidence of insulin resistance (HOMA-IR > or =2.5) in Groups A and B was significantly higher than in Group C. Regular doses of telmisartan and olmesartan significantly improved HOMA-IR and ALT levels not only in NAFLD patients but also in patients with CH-C. The effects tended to be more notable with telmisartan. In conclusion, telmisartan and olmesartan improved insulin sensitivity and may possibly be used as liver protecting agents in CH-C as well as NAFLD patients.
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PMID:Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: a pilot study. 1881 60

Insulin resistance (IR) and obesity may be associated with impaired response to physical exercise. We aimed at assessing physical capacity in obese children with biopsy proven non-alcoholic fatty liver disease (NAFLD) as compared to normal weight and obese children without fatty liver disease. All male subjects, 20 NAFLD and 31 control individuals (20 obese, without NAFLD and 11 normal weight children) took part in the study. We evaluated changes in cardiovascular parameters during a bicycle-ergometer exercise test (James' test). Duration, power of exercise, heart rate (HR), blood pressure (BP), pulse pressure, cardiac output ((I)CO) and total peripheral vascular resistance indexed for height ((I)TPVR) were recorded at rest ((r)) and peak ((p)) exercise. The homeostatic model assessment was used to determine insulin resistance (HOMA-IR) and beta-cell action (HOMA-beta cell). In NAFLD and obese subjects, fasting leptin, insulin secretion, insulinogenic index (IGI), muscle insulin sensitivity (MISI) and hepatic insulin resistance index (HIRI) were assayed. Children with NAFLD were the most insulin-resistant (P = 0.001), and showed higher HIRI than obese controls (P = 0.05). At rest, they had the lowest values of SBP(r) (P = 0.001 vs. controls and P < or = 0.05 vs. obese controls); during the test, the highest values of (I)CO(p) (P = 0.005), Delta(I)CO (P = 0.003) and DeltaTRVP(p) (P < or = 0.0001). NAFLD and obese controls both had impaired DeltaHR(p) (P < or = 0.0001). However, obese controls were not able to reduce peripheral resistance during the test. HOMA-IR explained 28% of variance in Delta(I)CO of the whole sample, (P < or = 0.0001). In obese children with or without NAFLD, increased IR and body weight may induce cardiovascular compensatory changes in response to physical exercise with fairly different pathogenetic mechanisms, which are likely to be dependent on the different degree of IR.
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PMID:Insulin resistance and exercise capacity in male children and adolescents with non-alcholic fatty liver disease. 1883 55

As little as 10 years ago, there was scepticism as to weather non-alcoholic fatty liver disease is a clinical condition. With the increasing prevalence of obesity, diabetes mellitus and the metabolic syndrome in the general population, non-alcoholic fatty liver disease has become a household diagnosis in clinical practice of several medical specialities. Meanwhile, it is the primary cause for elevated liver enzymes of unknown cause in clinical practice. Treatment is focused on the improvement of insulin resistance and of antioxidative mechanisms, mainly by life-style modifications including weight loss and exercise. Drug therapy cannot be recommended at this time, because studies showing positive effects on morbidity and mortality are still lacking. In addition, issues concerning long term safety and side effects of drugs still have to be resolved.
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PMID:[Are there therapeutic approaches of non-alcoholic fatty liver disease and its complications?]. 1900 23

Fatty liver (steatosis) is highly prevalent in China and is more often linked to obesity than to alcoholism. Among more affluent regions of China, the community prevalence of non-alcoholic fatty liver disease (NAFLD) is approximately 15%. With the increasing pandemic of obesity, the prevalence of NAFLD has approximately doubled in the past decade. The risk factors resemble those in other ethnic populations, but it is important to note that ethnic-specific definitions of central obesity, obesity and metabolic syndrome are more useful in assessment of Chinese people. The full range of histological manifestations of NAFLD has been demonstrated in Chinese patients, but to date hepatic severity is generally mild. In contrast to chronic hepatitis C, steatosis is less common in patients with chronic hepatitis B; it is associated with metabolic, and not viral factors and does not appear to affect disease severity. Although long-term outcomes of NAFLD in Chinese populations remain unclear, it may be a predictor of metabolic disorders, diabetes and cardiovascular disease. Public health interventions are therefore indicated to halt or reverse the national trend of obesity in China so as to improve liver as well as metabolic health.
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PMID:Epidemiology of non-alcoholic fatty liver disease in China. 1901 78


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