Showing papers by "Andreas L. Birkenfeld published in 2013"

Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance

Abstract: We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat–fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes.

Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease

Abstract: Objective: Adipose tissue-derived factors link non-alcoholic fatty liver disease (NAFLD) with obesity, which has also been reported for circulating chemerin. On the other hand, hepatic chemerin and chemokine-like receptor 1 (CMKLR1) mRNA expression has not yet been studied in an extensively characterized patient collective. Design: This study was cross-sectional and experimental in design. Methods: Liver tissue samples were harvested from 47 subjects and histologically examined according to the NAFLD activity score (NAS). The concentrations of chemerin and CMKLR1 were measured using semi-quantitative real-time PCR, and the concentration of serum chemerin was measured using ELISA. To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)). Results: Chemerin and CMKLR1 mRNA levels were elevated in the human liver. Their expression was correlated with the NAS (R 2 Z0.543; P!0.001 and R 2 Z0.355; PZ0.014 respectively) and was significantly elevated in patients with definite non-alcoholic steatohepatitis (NASH) (P!0.05 respectively). Linear regression analysis confirmed an independent association of liver fibrosis, steatosis, inflammation, and hepatocyte ballooning with hepatic chemerin mRNA expression (P!0.05 respectively). The expression of hepatic chemerin and CMKLR1 was correlated with the measures of obesity (P!0.05). The incubation of PHHs with IL6 significantly increased the expression of CMKLR1 mRNA (PZ0.027), while that of chemerin remained unaffected (PO0.05). None of the other metabolites showed an influence (PO0.05). Conclusion: This is the first study to show that chemerin mRNA expression is significantly elevated in the liver of NASH patients and that CMKLR1 expression is upregulated in liver inflammation, whereby IL6 could play a causal role.

Long-Lasting Improvements in Liver Fat and Metabolism Despite Body Weight Regain After Dietary Weight Loss

Abstract: OBJECTIVE Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known. RESEARCH DESIGN AND METHODS We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m 2 ; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17–36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance. RESULTS Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline. CONCLUSIONS A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions.

The Role of INDY in Metabolic Regulation

Abstract: Reduced expression of the Indy (I'm Not Dead Yet) gene in D. melanogaster and C. elegans extends longevity. Indy and its mammalian homolog mINDY (Slc13a5, NaCT) are transporters of TCA cycle intermediates, mainly handling the uptake of citrate via the plasma membrane into the cytosol. Deletion of mINDY in mice leads to significant metabolic changes akin to caloric restriction, likely caused by reducing the effects of mINDY-imported citrate on fatty acid and cholesterol synthesis, glucose metabolism and s-oxidation. This review will provide an overview on different mammalian SLC1 3 family members with a focus on mINDY (SLCl3A5) in glucose and energy metabolism and will highlight the role of mINDY as a putative therapeutic target for the treatment of obesity, non-alcoholic fatty liver disease and type 2 diabetes.

Comment on: Lazo et al. NH2-terminal pro-brain natriuretic peptide and risk of diabetes. Diabetes 2013;62:3189-3193.

Abstract: Lazo et al. (1) reported that plasma NH2-terminal pro–brain natriuretic peptide (NT-proBNP) levels, a cleavage product of brain natriuretic peptide (BNP), are inversely associated with diabetes risk in ∼7,800 healthy patients over a period of 12 years. In line with this, genetic evidence suggests a protective effect of BNP on diabetes risk (2). So far, mechanistic insight is lacking on how natriuretic peptides (NPs) …

How High-Density Lipoprotein Fuels the Failing Heart

Abstract: See related article, pp 1002–1007 Heart failure remains a major multifactorial health problem in the aging population.1 The causal cellular mechanisms are still incompletely understood, and further understanding of these mechanisms in heart failure is necessary to open up new perspectives for treatment and prevention. Distinct evidence suggests that cardiac energy metabolism in the failing heart is severely impaired.1,2 In fact, compromised cardiac energy metabolism might cause and worsen myocardial dysfunction. A growing body of evidence suggests that cellular energy sustenance in the diseased heart is crucial for understanding and treating cardiac dysfunction and thus needs to be investigated further. Nakajima et al3 now provide novel insights in the regulatory changes of cellular substrate use in the pathogenesis of heart failure. Vast amounts of energy are required to fuel the perpetual pumping activity of the heart. Although the fetal heart predominantly generates ATP from carbohydrate oxidation, the adult human heart draws on free-fatty acids as the major substrate for energy supply.4 Approximately 60% to 90% of the ATP required is generated by β-oxidation of long chain fatty acids. The remaining 10% to 40% are obtained by oxidation of other substrates, such as glucose, lactate, and ketone bodies.1 So far, evidence has indicated that fatty acid demand in cardiac β-oxidation is covered by hydrolysis of intramyocardial triglyceride storages, dissociation of circulating albumin-bound fatty acid complexes derived from adipose tissue-lipolysis, and lipoprotein lipase (LPL)–mediated hydrolysis of triglycerides within gut-derived chylomicrons, as well as liver-derived triglyceride-rich very low–density lipoproteins. In the failing heart, fatty acid use is impaired, resulting in a relative metabolic shift away from fatty acids to glucose oxidation in advanced heart failure.4 This condition might be owed to a more favorable ATP production to oxygen consumption ratio in glucose oxidation compared with …