Maternal Hyperleptinemia Improves Offspring Insulin Sensitivity in Mice

Maternal obesity and gestational diabetes are prevalent worldwide. Offspring of mothers with these conditions weigh more and are predisposed to metabolic syndrome. A hallmark of both conditions is maternal hyperleptinemia, but the role of elevated leptin levels during pregnancy on developmental programming is largely unknown. We previously found that offspring of hyperleptinemic mothers weighed less and had increased activity. The goal of this study was to determine whether maternal leptin affects offspring insulin sensitivity by investigating offspring glucose metabolism and lipid accumulation. Offspring from two maternal hyperleptinemic models were compared. The first model of hyperleptinemia is the Leprdb/+ mouse, which has a mutation in one copy of the gene that encodes the leptin receptor, resulting in a truncated long form of the receptor, and hyperleptinemia. Wild-type females served as the control for the Leprdb/+ females. For the second hyperleptinemic model, wild-type females were implanted with miniosmotic pumps, which released leptin (350 ng/h) or saline (as the control) just prior to mating and throughout gestation. In the offspring of these dams, we measured glucose tolerance; serum leptin, insulin, and triglyceride levels; liver triglycerides; pancreatic α- and β-cell numbers; body composition; incidence of nonalcoholic fatty liver disease; and the expression of key metabolic genes in the liver and adipose tissue. We found that the offspring of hyperleptinemic dams exhibited improved glucose tolerance, reduced insulin and leptin concentrations, reduced liver triglycerides, and a lower incidence of nonalcoholic fatty liver disease. Overall, maternal hyperleptinemia was beneficial for offspring glucose and lipid metabolism.

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Relationships between Parameters of Insulin Sensitivity, Obesity and Liver Aminotransferases in Patients with Nonalcoholic Fatty Liver Disease

Hungarian Medical Journal ◽

10.1556/hmj.1.2007.4.16 ◽

2007 ◽

Vol 1 (4) ◽

pp. 537-545

Author(s):

Emil Fraenkel ◽

Ivica Lazúrová ◽

Peter Jarčuška ◽

János Fehér ◽

József Hamvas

Keyword(s):

Liver Disease ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver

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Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease

Journal of Applied Physiology ◽

10.1152/japplphysiol.00127.2012 ◽

2012 ◽

Vol 113 (1) ◽

pp. 1-6 ◽

Cited By ~ 50

Author(s):

Ciaran E. Fealy ◽

Jacob M. Haus ◽

Thomas P. J. Solomon ◽

Mangesh Pagadala ◽

Chris A. Flask ◽

...

Keyword(s):

Liver Disease ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Fat Oxidation ◽

Whole Body ◽

Hepatocyte Apoptosis ◽

Short Term ◽

Nonalcoholic Fatty Liver

Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis—plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)—in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m2, >5% intrahepatic lipid (IHL) assessed by 1H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ∼85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (V̇o2max) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = −0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity.

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The kielin/chordin-like protein KCP attenuates nonalcoholic fatty liver disease in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00165.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. G587-G598 ◽

Cited By ~ 4

Author(s):

Abdul Soofi ◽

Katherine I. Wolf ◽

Egon J. Ranghini ◽

Mohammad A. Amin ◽

Gregory R. Dressler

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Liver Pathology ◽

Wild Type ◽

High Fat ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and is increasing with the rising rate of obesity in the developed world. Signaling pathways known to influence the rate of lipid deposition in liver, known as hepatic steatosis, include the transforming growth factor (TGF) superfamily, which function through the SMAD second messengers. The kielin/chordin-like protein (KCP) is a large secreted protein that can enhance bone morphogenetic protein signaling while suppressing TGF-β signaling in cells and in genetically modified mice. In this report, we show that aging KCP mutant ( Kcp −/−) mice are increasingly susceptible to developing hepatic steatosis and liver fibrosis. When young mice are put on a high-fat diet, Kcp −/− mice are also more susceptible to developing liver pathology, compared with their wild-type littermates. Furthermore, mice that express a Pepck-KCP transgene ( Kcp Tg) in the liver are resistant to developing liver pathology even when fed a high-fat diet. Analyses of liver tissues reveal a significant reduction of P-Smad3, consistent with a role for KCP in suppressing TGF-β signaling. Transcriptome analyses show that livers from Kcp −/− mice fed a normal diet are more like wild-type livers from mice fed a high-fat diet. However, the KCP transgene can suppress many of the changes in liver gene expression that are due to a high-fat diet. These data demonstrate that shifting the TGF-β signaling paradigm with the secreted regulatory protein KCP can significantly alter the liver pathology in aging mice and in diet-induced NAFLD.

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Therapeutic Targeting of Nonalcoholic Fatty Liver Disease by Downregulating SREBP-1C Expression via AMPK-KLF10 Axis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.751938 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yu-Chi Chen ◽

Rong-Jane Chen ◽

Szu-Yuan Peng ◽

Winston C. Y. Yu ◽

Vincent Hung-Shu Chang

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Target Genes ◽

Regulatory Element ◽

Wild Type ◽

Nonalcoholic Fatty Liver

Krüppel-like factor 10 (KLF10) is a phospho-regulated transcriptional factor involved in many biological processes including lipogenesis; however, the transcriptional regulation on lipogenesis by KLF10 remains largely unclear. Lipogenesis is important in the development of nonalcoholic fatty liver disease (NAFLD) which was known regulated mainly by AMP-activated protein kinase (AMPK) and sterol regulatory element-binding protein (SREBP-1C). Interesting, our previous study using phosphorylated site prediction suggested a regulation of AMPK on KLF10. Therefore, we aimed to study the protein–protein interactions of AMPK on the regulation of KLF10, and to delineate the mechanisms of phosphorylated KLF10 in the regulation of NAFLD through SREBP-1C. We performed in vitro and in vivo assays that identified AMPK phosphorylates KLF10 at Thr189 and subsequently modulates the steady state level of KLF10. Meanwhile, a chromatin immunoprecipitation–chip assay revealed the novel target genes and signaling cascades of corresponding to phosphorylated KLF10. SREBP-1C was identified as a target gene suppressed by phosphorylated KLF10 through promoter binding. We further performed high-fat-diet-induced NAFLD models using hepatic-specific KLF10 knockout mice and wild-type mice and revealed that KLF10 knockout markedly led to more severe NAFLD than that in wild-type mice. Taken together, our findings revealed for the first time that AMPK activates and stabilizes the KLF10 protein via phosphorylation at Thr189, thereby repressing the expression of SREBP-1C and subsequent lipogenesis pathways along with metabolic disorders. We suggested that the targeted manipulation of liver metabolism, particularly through increased KLF10 expression, is a potential alternative solution for treating NAFLD.

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