Prolonged exercise of medium to high intensity is known to promote a substantial effect on the energy balance of rats. In male rats, moderately to severely intense programs lead to a reduction in ...food intake. However, the exact causes for the appetite-suppressive effects of exercise are not known. Here, we show that intracerebroventricular insulin or leptin infusion reduced food intake in exercised rats to a greater extent than that observed in control animals. Exercise was associated with a markedly increased phosphorylation/activity of several proteins involved in leptin and insulin signal transduction in the hypothalamus. The regulatory role of interleukin (IL)-6 in mediating the increase in leptin and insulin sensitivity in hypothalamus was also investigated. Treatment with insulin or leptin markedly reduced food intake in exercised rats that were pretreated with vehicle, although no increase in sensitivity to leptin- and insulin-induced anorexia after pretreatment with anti-IL-6 antibody was detected. The current study provides direct measurements of leptin and insulin signaling in the hypothalamus and documents increased sensitivity to these hormones in the hypothalamus of exercised rats in an IL-6-dependent manner. These findings provide support for the hypothesis that the appetite-suppressive actions of exercise may be mediated by the hypothalamus.
AMP-activated protein kinase (AMPK) and mammalian Target of Rapamycin (mTOR) are key regulators of cellular energy balance and of the effects of leptin on food intake. Acute exercise is associated ...with increased sensitivity to the effects of leptin on food intake in an IL-6-dependent manner. To determine whether exercise ameliorates the AMPK and mTOR response to leptin in the hypothalamus in an IL-6-dependent manner, rats performed two 3-h exercise bouts, separated by one 45-min rest period. Intracerebroventricular IL-6 infusion reduced food intake and pretreatment with AMPK activators and mTOR inhibitor prevented IL-6-induced anorexia. Activators of AMPK and fasting increased food intake in control rats to a greater extent than that observed in exercised ones, whereas inhibitor of AMPK had the opposite effect. Furthermore, the reduction of AMPK and ACC phosphorylation and increase in phosphorylation of proteins involved in mTOR signal transduction, observed in the hypothalamus after leptin infusion, were more pronounced in both lean and diet-induced obesity rats after acute exercise. Treatment with leptin reduced food intake in exercised rats that were pretreated with vehicle, although no increase in responsiveness to leptin-induced anorexia after pretreatment with anti-IL6 antibody, AICAR or Rapamycin was detected. Thus, the effects of leptin on the AMPK/mTOR pathway, potentiated by acute exercise, may contribute to appetite suppressive actions in the hypothalamus.
Background & Aims Epidemiology studies have shown that obesity increases risk for colorectal cancer (CRC). We investigated the contribution of obesity-induced increases in levels of tumor necrosis ...factor (TNF)-α and hyperinsulinemia to the development of CRC in mice. Methods Lean and obese mice (C57BL6/J and ob/ob ) were given a combination of azoxymethane and dextran sulfate sodium, which led to the development of CRC; lean and obese severe combined immunodeficient mice were injected with HT-29 cells. We analyzed the roles of TNF-α and insulin in the development of obesity-mediated CRC using immunoblot, immunohistochemical, and apoptosis assays. Results Genetic- and diet-induced obesity increased the incidence and size of tumors that developed after administration of azoxymethane and dextran sulfate sodium, compared with lean mice. HT-29 xenograft tumors grew more rapidly in obese than lean mice. Neutralization of TNF-α reduced activation of c-Jun N-terminal kinase, IκB kinase, and the phosphatidylinositol 3-kinase–Akt–mammalian target of rapamycin signaling pathway; it also reduced the growth and development of tumors in obese mice. Reducing levels of insulin levels had no effect on tumor growth in obese mice. Conclusions TNF-α contributes to colon tumor growth in obese mice. Reagents that inhibit TNF-α might prevent the development or progression of CRC in obese individuals.
Proper activation of phosphoinositide 3-kinase-Akt pathway is critical for the prevention of tumorigenesis. Recent data have characterized a negative feedback loop, wherein mammalian target of ...rapamycin (mTOR) blocks additional activation of the Akt/mTOR pathway through inhibition insulin receptor substrate 1 (IRS-1) function. However, the potential of IRS-1 inhibition during rapamycin treatment has not been examined. Herein, we show that IRS-1 antisense oligonucleotide and rapamycin synergistically antagonize the activation of mTOR in vivo and induced tumor suppression, through inhibition of proliferation and induction of apoptosis, in prostate cancer cell xenografts. These data demonstrate that the addition of agents that blocks IRS-1 potentiate the effect of mTOR inhibition in the growth of prostate cancer cell xenografts.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).
This article has been retracted at the request of the ...Editor-in-Chief and Deputy Editor-in-Chief following an investigation into the data that were presented in several figures within the article.
A number of images used in this article are believed to be duplicated images. The authors stated that they inadvertently inserted images of the wrong blots in several of the figures, resulting in the duplications; however, they did not address all of the concerns raised. Because the editors were no longer confident in the conclusions of the article based on these incorrect data, a decision was made to retract the paper.
All authors have been notified of this decision. The University of Campinas (UNICAMP) in São Paulo, Brazil was contacted regarding these concerns, but to date the journal has received no response.
BACKGROUND:Preoperative anemia is independently associated with adverse outcomes after general and cardiac surgery. Outcomes after breast reconstruction are not established. We assessed the effect of ...preoperative anemia on 30-day postoperative morbidity and length of hospital stay (LOS) in patients undergoing immediate breast reconstruction.
METHODS:We identified patients undergoing immediate breast reconstruction from 2008 to 2010 from the American College of Surgeons’ National Surgical Quality Improvement Program database (a prospective outcomes-based registry from hospitals worldwide). De-identified data were obtained for demographics, preoperative risk factors, 30-day morbidity, and LOS. Morbidity variables included flap/graft/prosthesis, cardiac, respiratory, neurological, urinary, wound, and venous thromboembolism outcomes. Logistic regression assessed the crude and adjusted effect of anemia (hematocrit <36%) on postoperative 30-day morbidity. Measures of central tendency of LOS were compared across increasing severities of anemia in patients developing adverse events versus controls.
RESULTS:The study population included 10,958 patients; 1556 (16.74%) had preoperative anemia. Crude odds ratio for 30-day morbidity was significantly higher in anemic patients, unadjusted odds ratio = 1.33 (P < 0.008). This prevailed after extensive adjustment for confounding, yielding an adjusted odds ratio = 1.38 (P < 0.03). Patients who experienced adverse effects had protracted LOS, and the presence of anemia significantly amplified this effect.
CONCLUSIONS:These data provide new insight into the effect of anemia in immediate breast reconstruction, demonstrating an independent association between preoperative anemia and 30-day morbidity. These findings suggest treating anemia when possible; however, prospective studies should explore the efficacy, safety, and cost-effectiveness of such treatments.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the ...request of the Editor-in-Chief and Deputy Editor-in-Chief following an investigation into the data that were presented in several figures within the article.
A number of images used in this article are believed to be duplicated images. The authors stated that they inadvertently inserted images of the wrong blots in several of the figures, resulting in the duplications; however, they did not address all of the concerns raised. Because the editors were no longer confident in the conclusions of the article based on these incorrect data, a decision was made to retract the paper.
All authors have been notified of this decision. The University of Campinas (UNICAMP) in São Paulo, Brazil was contacted regarding these concerns, but to date the journal has received no response.
Physical activity confers beneficial metabolic effects by inducing anti-inflammatory activity in the hypothalamus region of the brain in rodents, resulting in a reorganization of the set point of ...nutritional balance and reduced insulin and leptin resistance.
Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKβ activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKβ/NF-κB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKβ/NF-κB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKβ and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.
The hypothalamus is a brain region that gathers information on the body's nutritional status and governs the release of multiple metabolic signaling molecules such as insulin and leptin to maintain homeostasis. Overeating and obesity are associated with insulin and leptin resistance in the hypothalamus, and recent studies provide an intriguing link between inflammation and dysfunction of hypothalamic insulin and leptin signaling through activation of IKKβ, a key player in immune response, and endoplasmic reticulum (ER) stress. This means that strategies to reduce the aberrant activation of inflammatory signaling in the hypothalamus are of great interest to improve the central insulin and leptin action and prevent or treat related metabolic diseases. Using a combination of pharmacological, genetic, and physiological approaches, our study indicates that physical activity reorganizes the set point of nutritional balance through anti-inflammatory signaling mediated by interleukin (IL)-6 and IL-10 in the hypothalamus of rodents. Hence, IL-6 and IL-10 are important physiological contributors to the central insulin and leptin action mediated by exercise, linking it to hypothalamic ER stress and inflammation.
Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. ...Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer in HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 in DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral–host interaction.
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