Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and metabolic syndrome. Am J Physiol Endocrinol Metab 299: E685-E694, 2010. First published September 7, 2010; doi:10.1152/ajpendo.00283.2010.-As dietary exposure to fructose has increased over the past 40 years, there is growing concern that high fructose consumption in humans may be in part responsible for the rising incidence of obesity worldwide. Obesity is associated with a host of metabolic challenges, collectively termed the metabolic syndrome. Fructose is a highly lipogenic sugar that has profound metabolic effects in the liver and has been associated with many of the components of the metabolic syndrome (insulin resistance, elevated waist circumference, dyslipidemia, and hypertension). Recent evidence has also uncovered effects of fructose in other tissues, including adipose tissue, the brain, and the gastrointestinal system, that may provide new insight into the metabolic consequences of high-fructose diets. Fructose feeding has now been shown to alter gene expression patterns (such as peroxisome proliferator-activated receptor-␥ coactivator-1␣/␤ in the liver), alter satiety factors in the brain, increase inflammation, reactive oxygen species, and portal endotoxin concentrations via Toll-like receptors, and induce leptin resistance. This review highlights recent findings in fructose feeding studies in both human and animal models with a focus on the molecular and biochemical mechanisms that underlie the development of insulin resistance, hepatic steatosis, and the metabolic syndrome.

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Induction of endoplasmic reticulum (ER) stress was previously shown to impair hepatic apolipoprotein B100 (apoB) production by enhancing cotranslational and posttranslational degradation of newly synthesized apoB. Here, we report the involvement of autophagy in ER stress-induced degradation of apoB and provide evidence for a significant role of autophagy in regulating apoB biogenesis in primary hepatocyte systems. Induction of ER stress following short-term glucosamine treatment of McA-RH7777 cells resulted in significantly increased colocalization of apoB with green fluorescent protein-microtubuleassociated protein 1 light chain 3 (GFP-LC3), referred to as apoB-GFP-LC3 puncta, in a dose-dependent manner. Colocalization with this autophagic marker correlated positively with the reduction in newly synthesized apoB100. Treatment of McA-RH7777 cells with 4-phenyl butyric acid, a chemical ER stress inhibitor, prevented glucosamine-and tunicamycin-induced increases in GRP78 and phosphorylated eIF2a, rescued newly synthesized [ 35 S]-labeled apoB100, and substantially blocked the colocalization of apoB with GFP-LC3. Autophagic apoB degradation was also observed in primary rat and hamster hepatocytes at basal conditions as well as upon the induction of ER stress. In contrast, this pathway was inactive in HepG2 cells under ER stress conditions, unless proteasomal degradation was blocked with N-acetyl-leucinyl-leucinyl-norleucinal and the medium was supplemented with oleate. Transient transfection of McA-RH7777 cells with a wild-type protein kinase R-like ER kinase (PERK) complementary DNA resulted in dramatic induction of apoB autophagy. In contrast, transfection with a kinase inactive mutant PERK gave rise to reduced apoB autophagy, suggesting that apoB autophagy may occur via a PERK signaling-dependent mechanism. Conclusion: Taken together, these data suggest that induction of ER stress leads to markedly enhanced apoB autophagy in a PERK-dependent pathway, which can be blocked with the chemical chaperone 4-phenyl butyric acid. ApoB autophagy rather than proteasomal degradation may be a more pertinent physiological mechanism regulating hepatic lipoprotein production in primary hepatocytes. (HEPATOLOGY 2011; 53:1515-1525

Background: JAK2 mediates signaling by a number of cytokines in the liver. Results: Hepatic JAK2 KO mice developed spontaneous steatosis but were protected from high fat diet-induced steatohepaitits and insulin resistance. Conclusion: Hepatic JAK2 is required for the development of diet-induced steatohepatitis and glucose intolerance. Significance: Understanding the role of JAK2 in metabolism will provide insights into the pathogenesis of the metabolic syndrome.

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Acute caffeine ingestion increases serum NEFA and plasma adrenaline and decreases insulin sensitivity. Although frequently suggested, it is not known if a tolerance to these alterations in glucose homeostasis is developed in habitual caffeine consumers. Our objective was to determine whether acute caffeine ingestion continued to alter insulin, glucose, NEFA and adrenaline during an oral glucose tolerance test (OGTT) following 14 d of caffeine consumption. Twelve caffeine-naive young males underwent four OGTTs over a 4-week period. Subjects ingested a gelatin-filled placebo (PLA) capsule on the first trial day and 5 mg caffeine/kg body weight on the remaining three trial days (day 0, day 7, day 14) before a 2 h OGTT. Following day 0 and day 7, subjects were given six dosages of 5 mg caffeine/kg to consume per d between trials. Serum insulin and blood glucose area under the curve (AUC) were significantly elevated (P,0·05) v. PLA on day 0 (36 and 103 %, respectively) and were not different from PLA on day 7. On day 14, insulin AUC was 29 % greater than PLA (P, 0·05), and glucose was greater (P, 0·05) during the first hour, although the 50 % elevation in glucose AUC was not different from PLA. Before the OGTT, caffeine resulted in greater (P,0·05) serum NEFA and plasma adrenaline concentrations in all three caffeine trials, but both NEFA and adrenaline concentrations were decreased (P, 0·05) on day 14 v. day 0. Although 14 d of caffeine consumption by previously caffeine-naive subjects reduced its impact on glucose homeostasis, carbohydrate metabolism remained disrupted. Caffeine: Glucose homeostasis: Oral glucose tolerance testThe relationship between caffeine, insulin sensitivity and the risk of type 2 diabetes has received considerable recent attention 1 . Acutely, caffeine can decrease insulin sensitivity during a hyperinsulinaemic -euglycaemic clamp 2 -6 and an oral glucose tolerance test (OGTT) 7 -10 . On the other hand, recent epidemiological studies report an inverse relationship between coffee consumption and type 2 diabetes 11 -16 and measurements of glucose tolerance 17 -20 . Several of these studies 15 -18 have speculated that a lessening or tolerance of the acute negative effects of caffeine on glucose homeostasis occurs in habitual caffeine consumers. Central and peripheral tissues demonstrate various degrees of tolerance to caffeine 21 . For example, chronic caffeine use decreased the acute effect of caffeine on mean arterial pressure and adrenaline concentrations, but not middle cerebral artery velocity 22 . Similarly, some individuals develop tolerance to the pressor effects of caffeine, albeit incomplete, while others do not 23,24 and still others demonstrate no change in blood pressure with chronic caffeine consumption 25 . To our knowledge no one has examined whether the influences of caffeine on carbohydrate homeostasis following an acute challenge is affected by daily intake of caffeine.It is appreciated that skeletal muscle is normally the main site of glucose disposal. Thong et al. ...