Liver but not adipose tissue is responsive to the pattern of enteral feeding

Pathologies including diabetes and conditions such as exercise place an unusual demand on liver energy metabolism, and this demand induces a state of energy discharge. Hepatic AMP-activated protein kinase (AMPK) has been proposed to inhibit anabolic processes such as gluconeogenesis in response to cellular energy stress. However, both AMPK activation and glucose release from the liver are increased during exercise. Here, we sought to test the role of hepatic AMPK in the regulation of glucose-producing and citric acid cycle-related fluxes during an acute bout of muscular work. We usedH/C metabolic flux analysis to quantify intermediary metabolism fluxes in both sedentary and treadmill-running mice. Additionally, liver-specific AMPK α1 and α2 subunit KO and WT mice were utilized. Exercise caused an increase in endogenous glucose production, glycogenolysis, and gluconeogenesis from phosphoenolpyruvate. Citric acid cycle fluxes, pyruvate cycling, anaplerosis, and cataplerosis were also elevated during this exercise. Sedentary nutrient fluxes in the postabsorptive state were comparable for the WT and KO mice. However, the increment in the endogenous rate of glucose appearance during exercise was blunted in the KO mice because of a diminished glycogenolytic flux. This lower rate of glycogenolysis was associated with lower hepatic glycogen content before the onset of exercise and prompted a reduction in arterial glucose during exercise. These results indicate that liver AMPKα1α2 is required for maintaining glucose homeostasis during an acute bout of exercise.

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“…Plasma insulin was evaluated by a double antibody method as performed previously (79). Plasma glucagon was assessed as reported (80).…”

Section: Blood Plasma and Tissue Metabolite Analysesmentioning

confidence: 99%

Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice

Hughey

James

Bracy

et al. 2017

Journal of Biological Chemistry

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“…This suggests that plasma TG levels are driven by the combined effects of hepatic and extrahepatic events. In contrast to adipose tissue, changes in the absolute rate of DNL in the liver are less responsive to rapid changes of glucose and/or insulin that might occur throughout the feeding-fasting cycle and are more tightly linked to the rate of substrate delivery to and uptake by the liver (66,67). An additional confounder is that many of the transcription factors that are important for DNL also affect hepatic carbohydrate metabolism and vice versa.…”

Section: De Novo Lipogenesismentioning

confidence: 99%

Pathway-selective Insulin Resistance and Metabolic Disease: The Importance of Nutrient Flux

Otero

Stafford

McGuinness

2014

Journal of Biological Chemistry

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Hepatic glucose and lipid metabolism are altered in metabolic disease (e.g. obesity, metabolic syndrome, and Type 2 diabetes). Insulin-dependent regulation of glucose metabolism is impaired. In contrast, lipogenesis, hypertriglyceridemia, and hepatic steatosis are increased. Because insulin promotes lipogenesis and liver fat accumulation, to explain the elevation in plasma and tissue lipids, investigators have suggested the presence of pathway-selective insulin resistance. In this model, insulin signaling to glucose metabolism is impaired, but insulin signaling to lipid metabolism is intact. We discuss the evidence for the differential regulation of hepatic lipid and glucose metabolism. We suggest that the primary phenotypic driver is altered substrate delivery to the liver, as well as the repartitioning of hepatic nutrient handling. Specific alterations in insulin signaling serve to amplify the alterations in hepatic substrate metabolism. Thus, hyperinsulinemia and its resultant increased signaling may facilitate lipogenesis, but are not the major drivers of the phenotype of pathway-selective insulin resistance.Metabolic disease (i.e. obesity, metabolic syndrome, and Type 2 diabetes) is characterized by altered glucose homeostasis, hyperinsulinemia, and hypertriglyceridemia. In the fasting state, the hyperglycemia and hyperinsulinemia are driven by a failure of insulin to augment muscle glucose uptake and restrain hepatic glucose production. In the fed state, this insulin resistance results in a failure of the liver to switch from glucose production to glucose disposal, contributing to the exaggerated hyperglycemia. Hyperinsulinemia is thought to be driven by the accompanying insulin resistance in multiple tissues including liver, muscle, adipose tissue, vasculature, and the brain. Although overall brain glucose uptake is not regulated by insulin, specific regions in the brain can become resistant to insulin. This modifies neural circuits that regulate the insulin response of the liver and other peripheral tissues, thereby exacerbating hyperinsulinemia and impaired glucose metabolism (1).The role of insulin resistance with regard to hepatic lipid metabolism is more complex. Insulin is required for hepatic lipid synthesis. Thus, one might hypothesize that hepatic insulin resistance would decrease hepatic triglyceride synthesis and therefore plasma triglycerides. In contrast, liver and plasma triglycerides are increased in metabolic disease. To resolve this paradox, investigators have proposed that there may be pathway-selective insulin resistance, which has been observed in vascular tissues (2-4). This would suggest that there are distinct insulin-sensitive signaling pathways that independently modulate glucose and lipid metabolism. Moreover, the model proposes that the pathways are differentially altered in metabolic disease. With selective insulin resistance, insulin fails to adequately suppress hepatic glucose production or augment hepatic glucose uptake, and yet still augments or at least sustains hepatic li...

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“…It is secreted into the circulation mainly from the liver, and also from pancreas and adipose tissue (Kharitonenkov et al, 2005; Otero et al, 2014; Potthoff et al, 2009). Additionally, cardiomyocytes secrete FGF21 in basal conditions (Planavila et al, 2013) and in response to cardiomyopathy and heart failure and upon cardiac stress (Dogan et al, 2014; Planavila et al, 2015).…”

Section: Metabolic Sensors In Agingmentioning

confidence: 99%

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

Navas-Enamorado

Bernier

Brea-Calvo

et al. 2017

Ageing Research Reviews

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Liver but not adipose tissue is responsive to the pattern of enteral feeding

Cited by 5 publications

References 33 publications

Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice

Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice

Pathway-selective Insulin Resistance and Metabolic Disease: The Importance of Nutrient Flux

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

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