scholarly journals Hepatocyte-specific Hepatocyte Nuclear Factor 4 alpha (HNF4) deletion decreases resting energy expenditure by disrupting lipid and carbohydrate homeostasis

2021 ◽  
Author(s):  
Ian Huck ◽  
E. Matthew Morris ◽  
John Thyfault ◽  
Udayan Apte
Keyword(s):  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Energy Utilization ◽  
Lipid Absorption ◽  
Whole Body ◽  
Positive Energy ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4 ◽  
Body Energy

Hepatocyte Nuclear Factor 4 alpha (HNF4α) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4α in metabolism, its overall role in whole body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4α deletion (HNF4α-KO) in mice on whole body energy expenditure (EE) and substrate utilization in fed, fasted, and high fat diet (HFD) conditions. HNF4α-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4α-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4α-KO mice were able to upregulate lipid oxidation during HFD suggesting that their metabolic flexibility was intact. However, only hepatocyte specific HNF4α-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4α-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic Beta-oxidation in HNF4α-KO livers across all feeding conditions. Together, our data suggest deletion of hepatic HNF4α increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole body energy expenditure. These data clarify the role of hepatic HNF4α on systemic metabolism and energy homeostasis.

scholarly journals Hepatocyte-Specific Hepatocyte Nuclear Factor 4 alpha (HNF4α) Deletion Decreases Resting Energy Expenditure By Disrupting Lipid and Carbohydrate Homeostasis

2018 ◽  
Author(s):  
Ian Huck ◽  
E. Matthew Morris ◽  
John Thyfault ◽  
Udayan Apte
Keyword(s):  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Energy Utilization ◽  
Lipid Absorption ◽  
Whole Body ◽  
Positive Energy ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4 ◽  
Body Energy

AbstractHepatocyte Nuclear Factor 4 alpha (HNF4α) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4α in metabolism, its overall role in whole body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4α deletion (HNF4α-KO) in mice on whole body energy expenditure (EE) and substrate utilization in fed, fasted, and high fat diet (HFD) conditions. HNF4α-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4α-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4α-KO mice were able to upregulate lipid oxidation during HFD suggesting that their metabolic flexibility was intact. However, only hepatocyte specific HNF4α-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4α-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic β-oxidation in HNF4α-KO livers across all feeding conditions. Together, our data suggest deletion of hepatic HNF4α increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole body energy expenditure. These data clarify the role of hepatic HNF4α on systemic metabolism and energy homeostasis.

scholarly journals The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Romain Girard ◽  
Sarah Tremblay ◽  
Christophe Noll ◽  
Stéphanie St-Jean ◽  
Christine Jones ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adipose Tissue ◽  
Lipid Metabolism ◽  
White Adipose Tissue ◽  
Whole Body ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Diet Induced Obesity ◽  
Regulatory Circuit ◽  
Body Energy

AbstractThe transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.

scholarly journals Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption

2017 ◽  
Vol 313 (2) ◽  
pp. E121-E133 ◽  
Author(s):  
Enrico Bertaggia ◽  
Kristian K. Jensen ◽  
Jose Castro-Perez ◽  
Yimeng Xu ◽  
Gilbert Di Paolo ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Hepatic Steatosis ◽  
Energy Homeostasis ◽  
Body Weight Gain ◽  
Western Diet ◽  
Lipid Absorption ◽  
Whole Body ◽  
Diabetes Therapy ◽  
Body Energy

Bile acids (BAs) are cholesterol derivatives that regulate lipid metabolism, through their dual abilities to promote lipid absorption and activate BA receptors. However, different BA species have varying abilities to perform these functions. Eliminating 12α-hydroxy BAs in mice via Cyp8b1 knockout causes low body weight and improved glucose tolerance. The goal of this study was to determine mechanisms of low body weight in Cyp8b1−/− mice. We challenged Cyp8b1−/− mice with a Western-type diet and assessed body weight and composition. We measured energy expenditure, fecal calories, and lipid absorption and performed lipidomic studies on feces and intestine. We investigated the requirement for dietary fat in the phenotype using a fat-free diet. Cyp8b1−/− mice were resistant to Western diet-induced body weight gain, hepatic steatosis, and insulin resistance. These changes were associated with increased fecal calories, due to malabsorption of hydrolyzed dietary triglycerides. This was reversed by treating the mice with taurocholic acid, the major 12α-hydroxylated BA species. The improvements in body weight and steatosis were normalized by feeding mice a fat-free diet. The effects of BA composition on intestinal lipid handling are important for whole body energy homeostasis. Thus modulating BA composition is a potential tool for obesity or diabetes therapy.

scholarly journals A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

Diabetologia ◽  
1997 ◽  
Vol 40 (7) ◽  
pp. 859-862 ◽  
Author(s):  
M. P. Bulman ◽  
M. J. Dronsfield ◽  
T. Frayling ◽  
M. Appleton ◽  
S. C. Bain ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
Hepatocyte Nuclear Factor 4 ◽  
Alpha Gene

Exercise and MEF2–HDAC interactions

2007 ◽  
Vol 32 (5) ◽  
pp. 852-856 ◽  
Author(s):  
Sean L. McGee
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Nuclear Export ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Positive Health ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase ◽  
Body Energy ◽  
Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

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