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Dietary Macronutrient Composition Directs ChREBP Isoform Expression and Glucose Metabolism in Mice.

ABSTRACT: Carbohydrate response element binding protein (ChREBP) is a lipogenic transcription factor that is thought to be involved in the development of hepatic steatosis and insulin resistance. Increased ChREBP expression in liver results in increased hepatic steatosis, and the isoform ChREBP? in adipose tissue can predict insulin sensitivity in obese humans. As ChREBP is activated by glucose, it was postulated that the composition of diet would regulate ChREBP isoform expression in metabolically relevant tissues. We compared the effects of diets with high complex carbohydrate, high fat, or a normal chow on ChREBP expression and metabolic parameters in C57BL/6 mice. We found that diets high in fat decrease ChREBP expression in adipose tissue, but isocaloric diets high in carbohydrate have no effect. Interestingly, this decrease in adipose ChREBP was associated with increased inflammatory markers. In the same animals a high carbohydrate diet induced a robust increase in hepatic ChREBP? expression (?2-fold; p = 0.0002), but little detectable change in the more abundant ChREBP? transcript. This change was accompanied by increased expression of target genes liver pyruvate kinase (p<0.0001), acetyl-CoA carboxylase (p = 0.0191) and stearoyl-CoA desaturase-1 (p = 0.0045). This increase in ChREBP expression was associated with increased hepatic steatosis, despite no changes in body weight or body fat when compared to chow-fed mice. Unexpectedly, mice fed a high carbohydrate diet displayed enhanced sensitivity to exogenous insulin, despite having mild glucose intolerance and increased liver steatosis. In summary, we have shown the composition of diet can selectively regulate ChREBP isoform expression in a tissue specific manner. Furthermore, we have shown a high complex carbohydrate diet selectively increases hepatic ChREBP? expression, which associates with hepatic steatosis but not insulin resistance. In contrast, a high fat diet reduces adipose ChREBP, which associates with inflammation and insulin resistance.

SUBMITTER: Jois T

PROVIDER: S-EPMC5167554 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Dietary Macronutrient Composition Directs ChREBP Isoform Expression and Glucose Metabolism in Mice.

Jois Tara T Howard Victor V Youngs Kristina K Cowley Michael A MA Sleeman Mark W MW

PloS one 20161219 12

Carbohydrate response element binding protein (ChREBP) is a lipogenic transcription factor that is thought to be involved in the development of hepatic steatosis and insulin resistance. Increased ChREBP expression in liver results in increased hepatic steatosis, and the isoform ChREBPβ in adipose tissue can predict insulin sensitivity in obese humans. As ChREBP is activated by glucose, it was postulated that the composition of diet would regulate ChREBP isoform expression in metabolically releva ...[more]

PMID: 27992582

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Project description:BACKGROUND:We sought to characterize the effects of dietary macronutrient composition on various hormones implicated in the regulation of insulin sensitivity (IS) and energy expenditure (EE). METHODS:Following 10-15% weight loss, 21 overweight subjects consumed 3 weight-loss maintenance diets [low fat (LF), low glycemic index (LGI) and very low carbohydrate (VLC)] in random order, each for 4 weeks. At baseline and at the end of each treatment period, fasting samples for fibroblast growth factor (FGF)-21, heme-oxygenase-1 (HO-1), chemerin, irisin, secreted frizzle-related protein (SFRP-4), total bile acids, ghrelin, gastrin inhibitory peptide (GIP), peptide-Y, and amylin; hepatic and peripheral IS; and EE were obtained. Analyses were controlled for age, gender, baseline body mass index, and diet sequence. RESULTS:FGF-21 decreased (P < 0.0001), with differential effect by macronutrient composition (mean change from baseline ± SEM: LF -49.4 ± 16.6, LGI -58.6 ± 16.3, VLC -76.7 ± 18.2 pg/mL, P = 0.0002). Change in FGF-21 was inversely associated with change in hepatic IS [Beta = -0.565 units/log(ng/mL), P = 0.02], but not with peripheral IS or EE. Heme-oxygenase-1 (HO-1) increased (P = 0.003), without differential effect by macronutrient composition (LF 0.40 ± 0.26, LGI 0.98 ± 0.63, VLC 0.49 ± 0.29 ng/mL, P = 0.07). Ghrelin increased (P = 0.0003), while chemerin decreased (P = 0.001) without macronutrient effect. Total bile acid, irisin, SFRP-4, GIP, peptide-Y and amylin levels did not change. CONCLUSIONS:FGF-21 levels decreased with dietary intervention in proportion to carbohydrate content, and correlated with hepatic insulin sensitivity, suggesting a pattern of improving FGF-21 resistance. HO-1 increased in response to dietary intervention, a tendency to greater increase in response to the LGI diet. Dietary intervention affected ghrelin and chemerin, independent of macronutrient composition. These findings may elucidate relationships between dietary composition, insulin sensitivity and metabolism. TRIAL REGISTRATION:NCT00315354.

Project description:BackgroundBroiler chickens are compulsive feeders that become obese as juveniles and are thus a unique model for metabolic disorders in humans. However, little is known about the relationship between dietary composition, fasting and refeeding and adipose tissue physiology in chicks. Our objective was to determine how dietary macronutrient composition and fasting and refeeding affect chick adipose physiology during the early post-hatch period.MethodsChicks were fed one of three isocaloric diets after hatch: high-carbohydrate (HC; control), high-fat (HF; 30% of ME from soybean oil) or high-protein (HP; 25% vs. 22% crude protein). At 4 days post-hatch, chicks were fed (continuous ad libitum access to food), fasted (3 h food withdrawal), or refed (fasted for 3 h and refed for 1 h). Subcutaneous, clavicular, and abdominal adipose tissue was collected for histological analysis and to measure gene expression, and plasma to measure non-esterified fatty acid (NEFA) concentrations (n = 6-10 per group).ResultsAdipose tissue weights were reduced in chicks that were fed the HP diet and adipocyte diameter was greater in the adipose tissue of chicks that ate the HF diet. Consumption of diets differing in protein and fat content also affected gene expression; mRNAs encoding fatty acid binding protein 4 and a lipolytic enzyme, monoglyceride lipase, were greater in chicks fed the HC and HF than HP diet in all three adipose tissue depots. Fasting influenced gene expression in a depot-dependent manner, where most fasting and refeeding-induced changes were observed in the clavicular fat of chicks that consumed the HC diet. Fasting increased plasma NEFA concentrations in chicks fed the HC and HP diets.ConclusionsThe decreased adipose tissue deposition in chicks fed the HP diet is likely explained by decreased rates of adipogenesis. Consumption of the HF diet was associated with greater adipose tissue deposition and larger adipocytes, likely as a result of greater rates of adipocyte hypertrophy. The depot-dependent effects of diet and fasting on gene expression may help explain mechanisms underlying metabolic distinctions among subcutaneous and visceral fat depots in humans.

Dataset Information

Dietary Macronutrient Composition Directs ChREBP Isoform Expression and Glucose Metabolism in Mice.

Publications

Dietary Macronutrient Composition Directs ChREBP Isoform Expression and Glucose Metabolism in Mice.

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