During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance. Transgenic mice overexpressing vascular endothelial growth factor (VEGF) in brown adipose tissue (BAT) and white adipose tissue (WAT) were generated. Vessel formation, metabolism, and inflammation were studied in VEGF transgenic mice and wild-type littermates fed chow or a high-fat diet. Overexpression of VEGF resulted in increased blood vessel number and size in both WAT and BAT and protection against high-fat diet–induced hypoxia and obesity, with no differences in food intake. This was associated with increased thermogenesis and energy expenditure. Moreover, whole-body insulin sensitivity and glucose tolerance were improved. Transgenic mice presented increased macrophage infiltration, with a higher number of M2 anti-inflammatory and fewer M1 proinflammatory macrophages than wild-type littermates, thus maintaining an anti-inflammatory milieu that could avoid insulin resistance. These studies suggest that overexpression of VEGF in adipose tissue is a potential therapeutic strategy for the prevention of obesity and insulin resistance.

Fructose makes up a significant proportion of energy intake in westernized diets; its increased consumption has paralleled the growing prevalence of obesity and metabolic syndrome over the past two decades. In the current study, we demonstrate that fructose administration (10% wt/vol) in the drinking water of rats reduces the trans-activating and trans-repressing activity of the hepatic peroxisome proliferator-activated receptor ␣ (PPAR␣). As a consequence, fructose decreases hepatic fatty oxidation and increases pro-inflammatory transcription factor nuclear factor B (NF-B) activity. These changes were not observed in glucose-administered rats (10% wt/ vol), although both carbohydrates produced similar changes in plasma adiponectin and in the hepatic expression of transcription factors and enzymes involved in fatty acid synthesis. Fructosefed, but not glucose-fed, rats were hyperleptinemic and exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) transcription factor, although they did not present a similar increase in the serine phosphorylation of nuclear STAT3. Thus, an impairment in the hepatic transduction of the leptin signal could be responsible for the observed alterations in PPAR␣ activity in fructose-fed rats. Because PPAR␣ activity is lower in human than in rodent liver, fructose ingestion in humans should cause even worse effects, which would partly explain the link between increased consumption of fructose and widening epidemics of obesity and metabolic syndrome. T he prevalence of metabolic syndrome and the risk for developing diabetes mellitus and cardiovascular disease is increasing worldwide. 1,2 Environmental factors (diet, physical activity), in tandem with predisposing genetic factors, may be responsible for this trend. Along with an increase in total energy consumption during recent decades, there has also been a shift in the types of nutrients, with an increased consumption of fructose, largely attributable to the greater intake of beverages containing high levels of fructose. 3 Once absorbed, dietary fructose is mainly taken up by the liver, promoting triacylglycerol synthesis and very low-density lipoprotein (VLDL) production. However, increases in liver fatty acid synthesis alone is not sufficient to account for such elevated triacylglycerol production. 4 Thus, those mechanisms underlying liver lipid metabolic derangements caused by high-fructose diets are not completely understood.The rat offers an effective model of human fructose metabolism. 5 A high-fructose diet in rats induces metabolic derangements similar to those found in the metabolic syndrome. 6 Nevertheless, although experimental designs using 50% to 60% of fructose in pelleted diets induce hypertriglyceridemia and a pronounced state of insulin resistance, 6,7 diets incorporating 10% wt/vol of fructose in drinking water induce hypertriglyceridemia and fatty liver without modifying plasma glucose and insulin levels. 8,9 Because high-carbohydrate diets and chronic hyperin...

There is controversy regarding whether fructose in liquid beverages constitutes another dietary ingredient of high caloric density or introduces qualitative changes in energy metabolism that further facilitate the appearance of metabolic diseases. Central to this issue is the elucidation of the molecular mechanism responsible for the metabolic alterations induced by fructose ingestion. Fructose administration (10% wt/vol) in the drinking water of Sprague-Dawley male rats for 14 days induced hyperleptinemia and hepatic leptin resistance. This was caused by impairment of the leptin-signal transduction mediated by both janus-activated kinase-2 and the mitogen-activated protein kinase pathway. The subsequent increase in activity in the liver of the unphosphorylated and active form of the forkhead box O1 nuclear factor, which transrepresses peroxisome proliferator-activated receptor ␣ activity, and a lack of activation of the adenosine monophosphate-activated protein kinase, led to hypertriglyceridemia and hepatic steatosis. These alterations are attributable to two key events: (1) F ructose makes up a significant proportion of energy in westernized diets, mainly due to the high intake of fructose-containing beverages. This situation has coincided with the growing prevalence of obesity and metabolic syndrome, recognized risk factors for cardiovascular diseases, over the past two decades. 1,2 Fructose in liquid diets induces hypertriglyceridemia to a greater extent than in solid diets. 3 A 10% dietary energy increase in

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Background: Human and animal studies have shown associations between insulin growth factor 2 (IGF2) and diabetes. Results: Overexpression of insulin growth factor 2 in ␤-cells leads to ␤-cell dysfunction and makes islets more vulnerable to ␤-cell damage and immune attack. Conclusion: IGF2 may play an important role in the predisposition and development of diabetes. Significance: This study unravels an unprecedented role of IGF2 on physiology of ␤-cells.

Electronegative low-density lipoprotein (LDL(-)) is a plasma-circulating LDL subfraction with proinflammatory properties that induces the production of chemokines in cultured endothelial cells. However, the specific mechanism of LDL(-)-mediated chemokine release is presently unknown. A characteristic feature of LDL(-) is an increased content of lysophosphatidylcholine (LPC) and non-esterified fatty acids (NEFA). The effect of increasing amounts of LPC and NEFA associated with LDL on the release of chemokines by endothelial cells was studied. Total LDL was subfractionated by anion-exchange chromatography in electropositive (LDL(+)) and LDL(-). LDL(-) contained two-fold more LPC and NEFA than LDL(+) and induced two- to four-fold more (p < 0.05) interleukin-8 (IL-8, 11.5 +/- 8.2 ng/10(5) cells) and monocyte chemotactic protein-1 (MCP-1, 10.8 +/- 3.8 ng/10(5) cells) release by human umbilical vein endothelial cells (HUVEC) than LDL(+) (IL-8: 3.4 +/- 1.5 ng/10(5) cells, MCP-1: 5.8 +/- 2.9 ng/10(5) cells). The content of LPC and NEFA in LDL(+) was increased by enzymatic treatment with secretory phospholipase A(2) (sPLA(2)) at 5 ng/mL or 20 ng/mL or by incubation with NEFA at 2 mmol/L. Modification of LDL(+) by both methods did not result in oxidative modification as demonstrated by the lack of change in antioxidants, conjugated dienes and malondialdehyde content. sPLA(2) treatment resulted in an increase in LPC and NEFA in LDL(+) which enhanced its ability to release IL-8 and MCP-1 by HUVEC in a concentration-dependent manner (sPLA(2)(5)-LDL; IL-8: 7.1 +/- 3.8ng/10(5) cells, MCP-1: 8.0 +/- 5.1 ng/10(5) cells; sPLA(2)(20)-LDL; IL-8: 20.8 +/- 11.2 ng/10(5) cells, MCP-1: 15.0 +/- 7.5 ng/10(5) cells). NEFA loading of LDL(+) also favored the release of IL-8 and MCP-1 (IL-8: 7.8 +/- 6.1 ng/10(5) cells, MCP-1: 8.4 +/- 2.7 ng/10(5) cells, p < 0.05 versus LDL(+)). These effects were observed when modified LDL(+) reached a content of LPC and/or NEFA similar that of LDL(-). These data indicate that non-oxidized polar lipids associated with LDL promote an inflammatory response in endothelial cells and suggest that increased NEFA and LPC could be involved in the inflammatory activity of LDL(-).

Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase–activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

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