Obesity is associated with an impaired immune response, an increased susceptibility to bacterial infection, and a chronic increase in proinflammatory cytokines such as IL-6 and TNFalpha. However, few studies have examined the effect of obesity on the immune response to viral infections. Because infection with influenza is a leading cause of morbidity and mortality worldwide, we investigated the effect of obesity on early immune responses to influenza virus exposure. Diet-induced obese and lean control C57BL/6 mice were infected with influenza A/PR8/34, and lung pathology and immune responses were examined at d 0 (uninfected), 3, and 6, postinfection. Following infection, diet-induced obese mice had a significantly higher mortality rate than the lean controls and elevated lung pathology. Antiviral and proinflammatory cytokine mRNA production in the lungs of the infected mice was markedly different between obese and lean mice. IFNalpha and beta were only minimally expressed in the infected lungs of obese mice and there was a notable delay in expression of the proinflammatory cytokines IL-6 and TNFalpha. Additionally, obese mice had a substantial reduction in NK cell cytotoxicity. These data indicate that obesity inhibits the ability of the immune system to appropriately respond to influenza infection and suggests that obesity may lead to increased morbidity and mortality from viral infections.

In vascular smooth muscle cells, the induction of early growth response genes involves the Janus kinase (JAK)/ signal transducer and activators of transcription (STAT) and the Ras/Raf-1/mitogen-activated protein kinase cascades. In the present study, we found that electroporation of antibodies against MEK1 or ERK1 abolished vascular smooth muscle cell proliferation in response to either platelet-derived growth factor or angiotensin II. However, anti-STAT1 or -STAT3 antibody electroporation abolished proliferative responses only to angiotensin II and not to platelet-derived growth factor. AG-490, a specific inhibitor of the JAK2 tyrosine kinase, prevented proliferation of vascular smooth muscle cells, complex formation between JAK2 and Raf-1, the tyrosine phosphorylation of Raf-1, and the activation of ERK1 in response to either angiotensin II or platelet-derived growth factor. However, AG-490 had no effect on angiotensin II-or platelet-derived growth factor-induced Ras/Raf-1 complex formation. Our results indicate that: 1) STAT proteins play an essential role in angiotensin II-induced vascular smooth muscle cell proliferation, 2) JAK2 plays an essential role in the tyrosine phosphorylation of Raf-1, and 3) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vascular smooth muscle cell proliferation in response to both growth factor and G protein-coupled receptors.Previous work by our laboratory (1-6) on cultured rat aortic vascular smooth muscle cells (VSMC) 1 and phenotypically similar glomerular mesangial cells has shown that protein tyrosine phosphorylation plays a critical role in angiotensin II (Ang II)-mediated intracellular signaling cascades. This is true despite the fact that G protein-coupled receptors in general and the Ang II AT 1 receptor in particular possess no intrinsic tyrosine kinase activity. It is also now recognized that Ang II can act not only as a vasoactive peptide but also as a growth factor. In particular, Ang II has been shown to stimulate proliferative and hypertrophic growth in VSMC, glomerular mesangial cells, cardiac fibroblasts, and myocytes via AT 1 receptor binding (4, 7-9). Like classic growth factors (e.g. platelet-derived growth factor (PDGF) and epidermal growth factor) and some cytokines (e.g. interferons and interleukins) (4, 8 -10), Ang II is also capable of stimulating a rapid increase in the mRNA levels of c-fos, an early growth response gene implicated in VSMC proliferation (4,7,8). However, the Ang II-stimulated intracellular signaling cascades responsible for c-fos induction and therefore proliferation in VSMC have not been well defined.One candidate mitogenic signaling cascade involves the activation of the small GTP-binding protein, Ras, which is traditionally mediated via classic growth factor receptors (4). Ras activation promotes the formation of a membrane-bound complex with Raf-1 (a serine/threonine protein kinase). Subsequent tyrosine phosphorylation of Raf-1 leads to its activation and the sequential stimulati...

Flavonoids, polyphenolic compounds that exist widely in plants, inhibit cell proliferation and increase cell differentiation in many cancerous and noncancerous cell lines. Because terminal differentiation of preadipocytes to adipocytes depends on proliferation of both pre- and postconfluent preadipocytes, we predicted that flavonoids would inhibit adipogenesis in the 3T3-L1 preadipocyte cell line. The flavonoids genistein and naringenin inhibited proliferation of preconfluent preadipocytes in a time- and dose-dependent manner. When added to 2-day postconfluent preadipocytes at the induction of differentiation, genistein inhibited mitotic clonal expansion, triglyceride accumulation, and peroxisome proliferator-activated receptor-gamma expression, but naringenin had no effect. The antiadipogenic effect of genistein was not due to inhibition of insulin receptor subtrate-1 tyrosine phosphorylation. When added 3 days after induction of differentiation, neither flavonoid inhibited differentiation. In fully differentiated adipocytes, genistein increased basal and epinephrine-induced lipolysis, but naringenin had no significant effects. These data demonstrate that genistein and naringenin, despite structural similarity, have differential effects on adipogenesis and adipocyte lipid metabolism.

An overactive renin-angiotensin system is associated with obesity and the metabolic syndrome. However, the mechanisms behind it are unclear. Cleaving angiotensinogen to angiotensin I by renin is a rate-limiting step of angiotensin II production, but renin is suggested to have angiotensin-independent effects. We generated mice lacking renin (Ren1c) using embryonic stem cells from C57BL/6 mice, a strain prone to diet-induced obesity. Ren1c(-/-) mice are lean, insulin sensitive, and resistant to diet-induced obesity without changes in food intake and physical activity. The lean phenotype is likely due to a higher metabolic rate and gastrointestinal loss of dietary fat. Most of the metabolic changes in Ren1c(-/-) mice were reversed by angiotensin II administration. These results support a role for angiotensin II in the pathogenesis of diet-induced obesity and insulin resistance.

Maximal weight loss observed in low-calorie diet (LCD) studies tends to be small, and the mechanisms leading to this low treatment efficacy have not been clarified. Less-than-expected weight loss with LCDs can arise from an increase in fractional energy absorption (FEA), adaptations in energy expenditure, or incomplete patient diet adherence. We systematically reviewed studies of FEA and total energy expenditure (TEE) in obese patients undergoing weight loss with LCDs and in patients with reduced obesity (RO), respectively. This information was used to support an energy balance model that was then applied to examine patient adherence to prescribed LCD treatment programs. In the limited available literature, FEA was unchanged from baseline in short-term (<12 wk) treatment studies with LCDs; no long-term (>or=26 wk) studies were found. Review of doubly labeled water and respiratory chamber studies identified 10 reports of TEE in RO patients (n = 150) with long-term weight loss. These patients, who were weight stable, had a TEE almost identical to measured or predicted values in never-obese subjects (weighted mean difference: 1.3%; range: -1.7-8.5%). Modeling of energy balance, as supported by reviewed FEA and TEE studies, suggests that obese subjects participating in LCD programs have a weight loss less than half of that predicted. The small maximal weight loss observed with LCD treatments thus is likely not due to gastrointestinal adaptations but may be attributed, by deduction, to difficulties with patient adherence or, to a lesser degree, to metabolic adaptations induced by negative energy balance that are not captured by the current models.