BACKGROUND:Both circadian disruption and timing of feeding have important roles in the development of metabolic disease. Despite growing acceptance that the timing of food consumption has long-term impact on metabolic homeostasis, little is known regarding the immediate influence on whole body metabolism, or the mechanisms involved. We aimed to examine the acute effects of time-of-day-dependent high fat feeding on whole body substrate metabolism and metabolic plasticity, and to determine the potential contribution of the adipocyte circadian clock. METHODS:Mice were fed a regimen of 4-h meal at the beginning and end of the dark (waking) cycle, separated by 4 h of fasting. Daily experimental conditions consisted of either an early very high fat or high fat (EVHF or EHF, 60 or 45% kcals from fat, respectively) or late (LVHF or LHF) meal, paired with a low fat (LF, 10% kcals from fat) meal. Metabolic parameters, glucose tolerance, body fat composition and weight were assessed. To determine the role of the adipocyte circadian clock, an aP2-CLOCK mutant (ACM) mouse model was used. RESULTS:Mice in the EVHF or EHF groups showed a 13.2 or 8.84 higher percentage of caloric intake from fat and had a 0.013 or 0.026 lower daily average respiratory exchange ratio, respectively, compared with mice eating the opposite feeding regime. Changes in glucose tolerance, body fat composition and weight were not significant at the end of the 9-day restricted feeding period. ACM mice did not exhibit different metabolic responses to the feeding regimes compared with wild-type littermates. Circadian clock disruption did not influence the short-term response to timed feeding. CONCLUSIONS:Both the total fat composition of diet and the timing of fat intake may differentially mediate the effect of timed feeding on substrate metabolism, but may not induce acute changes in metabolic flexibility.

The prevalence of obesity, an established risk factor for many chronic diseases, including several types of cancer, has risen steadily over the past four decades in the United States and worldwide. To date, research in this area has focused on the epidemiologic associations between obesity and cancer risk, as well as on the mechanisms underlying those associations. However, an emerging but understudied issue of clinical importance is the diminution of chemotherapeutic efficacy in obese cancer patients. The mechanisms underlying the negative impact of obesity on therapeutic responses are likely multifactorial. The effects of obesity on chemotherapy drug pharmacokinetics and dosage have been extensively reviewed elsewhere, so this review will focus on the interplay among obesity, increased inflammation, metabolic perturbations, and chemoresistance. The ultimate goal of this review is to delineate areas for future research that could lead to the identification of new targets and strategies for improved cancer outcomes in obese patients.

Abstract Background: In the U.S., the prevalence of obesity has reached epidemic proportions, with over two-thirds of the population being overweight and one-third being obese. Epidemiological data suggests that women who maintain a healthy weight have a lower risk of developing breast cancer and a better prognosis if diagnosed than those that are obese. Of the various breast cancer subtypes, claudin-low is associated with poor prognosis and resistance to standard chemotherapeutic regimens, Our lab has previously shown that a diet-induced obesity (DIO) regimen enhanced tumor progression and promoted the epithelial to mesenchymal transition (EMT)- and tumor–initiating cell (TIC)-associated markers in a murine claudin-low tumor model. Resveratrol is an antiinflammatory natural polyphenol that can decrease expression of markers indicative of stem cells and prevent EMT. Therefore, we hypothesized that resveratrol would impede the protumorigenic nature of obesity through its effects on EMT in a stem cell-enriched tumor model. The present study evaluated the effect of resveratrol supplementation on tumor growth in a DIO regimen in the murine M-Wnt breast cancer model. Methods: Eight-week-old ovariectomized female C57BL/6 mice were randomized (n = 15 per group) to receive one of the following three dietary regimens: control diet (10%kcal from fat), DIO regimen (60% kcal from fat), or DIO regimen supplemented with resveratrol (0.5% wt/wt). Mice consumed the experimental diets ad libitum for 6 weeks prior to orthotopic injection of 2.5×105 GFP-luciferase labeled M-Wnt murine mammary tumor cells (derived from MMTV-Wnt-1 tumor). Transplanted tumors grew for five additional weeks while diets were continued. Tumors were measured weekly with calipers and in vivo growth was monitored by the In Vivo Imaging System (IVIS). Mice were killed, serum was collected and stored at -80C and tissues were either fixed in 10% neutral-buffered saline or or flash-frozen. Results: Using the M-Wnt model of claudin-low breast cancer, we found that resveratrol supplementation significantly reduced body weight (p<0.0001), caloric intake (p<0.05) and tumor burden (weight and volume)(p = 0.021 and p = 0.007, respectively) within the DIO regimen although it had no effect on fasting glucose. Control maintained a significantly lower body fat percentage (p<0.001) than DIO regardless of resveratrol supplementation. Despite weighing significantly more (p<0.0001), mice that consumed the resveratrol-supplemented diet had comparable tumor burden to the lower calorie, control diet. Discussion: We conclude that resveratrol supplementation circumvented the protumorigenic nature of the DIO regimen equivalent to the lower calorie, lower fat control diet. Thus, dietary supplementation with resveratrol in the high-risk, obese population could break the obesity-cancer link. Keywords: epithelial to mesenchymal transition, resveratrol, mammary tumor, diet-induced obesity, stem cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-07.

1504 Background: Pancreatic cancer is the 4th leading cause of cancer death in both men and women in the U.S. Increased obesity has emerged as a risk factor for pancreatic cancer. Calorie restriction (CR), a dietary strategy that prevents or reverses obesity, has significant anti-cancer effects in a variety of tumor types and in both spontaneous and chemically-induced tumors. We have found in the K5.COX-2 transgenic mouse model of pancreatitis-driven pancreatic cancer that CR significantly protects from spontaneous pancreatic lesion formation as compared to the overweight and obese groups. Also, CR mice had significantly reduced serum IGF-1 levels and pro-inflammatory cytokine levels as compared to ad libitum fed (AL) and high fat (HF) fed mice. We hypothesized that decreased serum IGF-1 levels were responsible for the decreased tumor burden. Methods: Orthotopic injections were performed on 6–8 week old Liver-specific IGF-1- Deficient (LID) and control mice (FVB/N and floxed IGF-1) with pancreatic tumor cells (JC101) derived from a transgenic K5.COX-2 animal. Tumors and pancreata were harvested and weighed 28 days after tumor injection. Results: LID mice exhibited significantly reduced tumor burden (0.23±0.04) than either the floxed IGF-1 control (0.71±0.10) or FVB/N wild-type animals (0.71±0.04) following 28 days of growth. In addition to a reduction in serum IGF-1 in the LID mice, we also found a substantial decrease in serum levels of a panel of pro-inflammatory cytokines such as IFN-g, IL-1b, IL-4, IL-5, IL-10, IL-12, and TNF-a as compared to sera of control animals. Furthermore, we saw reduced proliferation and microvessel density in the tumor tissue of LID animals compared to controls by immunohistochemical staining. Conclusions: Using a model of pancreatitis-induced or orthotopically injected pancreatic tumorigenesis, our findings indicate that either transgenic manipulation or diet modulation of serum IGF-1 can alter the development of pancreatic cancer. Moreover, our findings suggest a strong link between expression of IGF-1 and pro-inflammatory cytokines in response to CR and the prevention of tumor growth. This could have direct implications for the prevention and control of pancreatic tumors due to chronic inflammation and/or obesity. No significant financial relationships to disclose.