Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease

Table 2 Pathophysiology of insulin resistance

Actions of insulin	Mechanism of action of insulin	Alterations in insulin resistant states	Net metabolic effect
(a) Stimulatory Increases glucose transport: In adipocytes In myocytes	-Insulin binds to its membrane receptor to cause up regulation of GLUT-4 via mediation of IRS-1/2(activated by phosphorylation at tyrosine sites)	-Impaired post receptor signaling involving IRS proteins -Abnormal phosphorylation of IRS-1 makes it inhibitor of the receptor kinase -Activation of IKK-β by free FA and cytokines leads to activation of NF-κB which further inhibits the genes involved in GLUT synthesis	-Hyperglycemia -Decreased glucose utilization as energy source -Reactive hyperinsulinemia
Increases glycogenesis In hepatocytes In myocytes	-By providing the building blocks -Increases expression and activity of glycogen synthase and inhibiting the glycogenolytic enzymes	-Decreased glycogen synthesis	-Hyperglycemia -Decreased postprandial glycogen stores in liver
Increases lipogenesis In adipose tissue In liver (DNL)	-Increases the supply of substrates -Postprandial stimulation of FAS, ACC and SCD1 -Increases supply of free FA in AT	-Further increase in lipogenesis,esp. DNL -Increased delivery of free FA to liver -Decreased oxidation in hepatocytes	-Excessive fat storage in AT and in other tissues (lipotoxicity) -Hepatic steatosis -Increased adiposity
Increases protein synthesis in muscles	-Activates the translational machinery -Activates protein kinase B which activates the protein synthesizing enzymes -In long term exposure increases ribosome in cells	-Decreased protein synthesis	-Sarcopenia
Increases glucose oxidative pathways	-Enhances glycolysis and Kreb's cycle by activating all the key regulator enzymes	-Inhibited -Lipid oxidation preferentially used for energy purposes	-Hyperglycemia -Oxidative stress in hepatocytes
(b) Inhibitory Decreases gluconeogenesis in liver	-Inhibits pyruvate carboxylase, glucose 6 phosphatase and PEP kinase -Shuttles substrates to lipogenesis	-Enhanced gluconeogenesis -Decreased inhibition of keyregulatory enzymes -Activation of AMPK	-Increased hepatic glucose output -Excessive availability of substrates for lipogenesis -Fasting hyperglycemia
Decreases hepatic glucose output	-Decreases gluconeogenesis -Increases glycogen synthesis -Increases oxidation of glucose	-Increased gluconeogenesis -Decreased glycogenesis and oxidative disposal of glucose	-Hyperglycemia
Suppresses lipolysis in adipose tissue	-Suppression of HSL	-Increased rate of free FA release in fasting state in lean and obese -When corrected for body weight in obese, postprandial lipolysis may seem to be normal or even decreased	-Increased plasma free FA both in fasting and post-prandial states(May be due to a mass effect of overall expansion of body fat depots in case of obese) -Increased free FA efflux -Increased VLDL
Decreases apolipoprotein secretion	-Insulin decreases the synthesis and secretion of Apo-B and Apo-C	-Hyperinsulinemia causes further suppression of expression of apolipoprotein genes and also inhibits post translational modifications and secretion -Enhanced synthesis of Apo-B 48 in intestines	-Trapping of TAG inside the liver -Hepatic steatosis -Increased VLDL
Suppresses β oxidation of fatty acids	-Insulin acts via binding to SREBP-1 transcription factor to cause increased expression of ACC-1 leading to generation of FAS substrates for lipogenesis	-Reactive hyperinsulinemia with unrestricted effect on SREBP causes further inhibition of β-oxidation of free FA in hepatocytes mitochondria	-Hepatic steatosis -CYP system over expression and generation of ROS

Hyperinsulinemia and hyperglycemia are two main net metabolic effects of IR. IR also contributes to expansion of NEFA pool and is now alone considered to be responsible for both the hits of 'two hit hypotheses' of NAFLD. IKK-β: Inhibitor of kappaB kinase beta; NF-κB: Nuclear factor-kappa B; FAS: Fatty acyl synthase; ACC: Acyl-CoA carboxylase; SCD: stearoyl-CoA desaturase; PEP: Phosphoenol pyruvate; CYP: Cytochrome P. FA: fatty acids; AT: adipose tissue; HSL: hormone sensitive lipase; SREBP: sterol regulatory element binding protein;IRS:receptor substrate proteins; GLUT: glucose transporter; AMPK: adenosine monophosphate kinase; ROS: reactive oxygen species.