The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by ...which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.
Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) ...mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.
Display omitted
► Adipocyte-specific NCoR knockout leads to derepression of PPARγ ► NCoR deletion decreases CDK5-mediated phosphorylation of PPARγ at serine 273 ► NCoR is an adaptor protein for CDK5-PPARγ association and ser 273 phosphorylation ► PPARγ derepression leads to insulin sensitivity and decreased inflammation
NCoR promotes the association of PPAR
γ with CDK5, leading to PPAR
γ phosphorylation and inactivation. Adipocyte-specific deletion of NCoR leads to constitutive activation of PPAR
γ in adipocytes and to improved insulin sensitivity in multiple tissues.
Intermittent Fasting and Human Metabolic Health Patterson, Ruth E., PhD; Laughlin, Gail A., PhD; LaCroix, Andrea Z., PhD ...
Journal of the Academy of Nutrition and Dietetics,
08/2015, Letnik:
115, Številka:
8
Journal Article
Total sedentary time varies across population groups with important health consequences. Patterns of sedentary time accumulation may vary and have differential health risks. The purpose of this study ...is to describe sedentary patterns of older adults living in retirement communities and illustrate gender and age differences in those patterns.
Baseline accelerometer data from 307 men and women (mean age = 84±6 years) who wore ActiGraph GT3X+ accelerometers for ≥ 4 days as part of a physical activity intervention were classified into bouts of sedentary time (<100 counts per minute). Linear mixed models were used to account for intra-person and site-level clustering. Daily and hourly summaries were examined in mutually non-exclusive bouts of sedentary time that were 1+, 5+, 10+, 20+, 30+, 40+, 50+, 60+, 90+ and 120+ minutes in duration. Variations by time of day, age and gender were explored.
Men accumulated more sedentary time than women in 1+, 5+, 10+, 20+, 30+, 40+, 50+ and 60+ minute bouts; the largest gender-differences were observed in 10+ and 20+ minute bouts. Age was positively associated with sedentary time, but only in bouts of 10+, 20+, 30+, and 40+ minutes. Women had more daily 1+ minute sedentary bouts than men (71.8 vs. 65.2), indicating they break up sedentary time more often. For men and women, a greater proportion of time was spent being sedentary during later hours of the day than earlier. Gender differences in intra-day sedentary time were observed during morning hours with women accumulating less sedentary time overall and having more 1+ minute bouts.
Patterns identified using bouts of sedentary time revealed gender and age differences in the way in which sedentary time was accumulated by older adults in retirement communities. Awareness of these patterns can help interventionists better target sedentary time and may aid in the identification of health risks associated with sedentary behavior. Future studies should investigate the impact of patterns of sedentary time on healthy aging, disease, and mortality.
Various microbial products leaked from gut lumen exacerbate tissue inflammation and metabolic disorders in obesity. Vsig4+ macrophages are key players preventing infiltration of bacteria and their ...products into host tissues. However, roles of islet Vsig4+ macrophages in the communication between microbiota and β cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in β cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into β cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into β cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in β cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in β cells and subsequently obesity-associated islet abnormalities.
Emerging evidence suggests that there is interplay between the frequency and circadian timing of eating and metabolic health. We examined the associations of eating frequency and timing with ...metabolic and inflammatory biomarkers putatively associated with breast cancer risk in women participating in the National Health and Nutrition Examination 2009-2010 Survey. Eating frequency and timing variables were calculated from 24-hour food records and included (1) proportion of calories consumed in the evening (5 pm-midnight), (2) number of eating episodes per day, and (3) nighttime fasting duration. Linear regression models examined each eating frequency and timing exposure variable with C-reactive protein (CRP) concentrations and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Each 10 percent increase in the proportion of calories consumed in the evening was associated with a 3 percent increase in CRP. Conversely, eating one additional meal or snack per day was associated with an 8 percent reduction in CRP. There was a significant interaction between proportion of calories consumed in the evening and fasting duration with CRP (p = 0.02). A longer nighttime fasting duration was associated with an 8 percent lower CRP only among women who ate less than 30% of their total daily calories in the evening (p = 0.01). None of the eating frequency and timing variables were significantly associated with HOMA-IR. These findings suggest that eating more frequently, reducing evening energy intake, and fasting for longer nightly intervals may lower systemic inflammation and subsequently reduce breast cancer risk. Randomized trials are needed to validate these associations.
We recently reported that stressed adipocytes release extracellular vesicles (EVs) that act as “find-me” signals to promote macrophage migration and activation. In this study, we performed a ...comprehensive characterization of stressed adipocyte-derived EVs, assessing their antigenic composition, lipidomics, and RNA profiles. Perilipin A was identified as one of the adipose-specific proteins and studied as a potential novel biomarker to detect adipocyte-derived EVs in circulation. Circulating EVs were significantly increased in mice with diet-induced obesity (DIO) and in obese humans with metabolic syndrome compared to lean controls. This increase was associated with decreased glucose tolerance in the DIO mice and metabolic dysfunction, elevated insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the obese humans. EVs from both DIO mice and obese humans were enriched in perilipin A, a central gatekeeper of the adipocyte lipid storehouse and a marker of adipocyte differentiation. In obese humans, circulating levels of EVs enriched in perilipin A were dynamic, decreasing 35 % (
p
< 0.05) after a 3-month reduced calorie diet intervention. This translational study provides an extensive characterization of adipocyte-derived EVs. The findings identify perilipin A as a novel biomarker of circulating EVs of adipocyte origin and support the development of circulating perilipin A-positive EVs as indicators of adipose tissue health.
Key message
• Extensive characterization of 3T3L1 EVs identified perilipin A in their composition.
• Circulating EVs are elevated in obese mice and associated with glucose intolerance.
• Circulating EVs are elevated in obese human and correlated with metabolic factors.
• Perilipin A and EV levels are increased in the circulation of obese mice and human.
• Circulating EV and perilipin A levels decrease with low calorie intervention.
Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers ...including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.
The association between sugar-sweetened beverage (SSB) consumption and colorectal cancer (CRC) risk remains unclear and published data are limited.
The analytic cohort included 99,798 women, free of ...cancer at baseline, from the California Teachers Study, a longitudinal cohort comprised of 133,477 female teachers and administrators who were active or recently retired members of the California State Teachers Retirement System in 1995. SSB consumption constituted caloric soft drinks, sweetened bottled waters and teas, and fruit drinks, derived from a self-administered food frequency questionnaire. Consumption was divided into four categories: Rare or never, >rare/never to <1 serving/week, ≥1 serving/week to <1 serving/day, and ≥1 serving/day. CRC endpoints were based on annual linkage with California Cancer Registry, defined as first diagnosis of CRC, and classified following the Surveillance, Epidemiology, and End Results Program coding system. Multivariable-adjusted Cox proportional hazards models were used to generate hazard ratios (HR) and 95% confidence intervals (CI) for assessing the association between SSB consumption and incident CRC.
A total of 1,318 incident CRC cases were identified over 20 years of follow-up (54.5% proximal colon and 45.5% distal colorectum). Compared with rare/never consumers, the multivariable-adjusted HRs (95% CI) were 1.14 (0.86, 1.53) for total CRC; 1.11 (0.73, 1.68) for proximal colon; and 1.22 (0.80, 1.86) for distal colorectum cancers among women consuming ≥ 1 serving/day of SSBs.
SSBs were not significantly associated with CRC risk. The biological effects of high SSB consumption make it important to continue to evaluate whether SSBs are associated with CRC. Additionally, future studies should further assess SSBs in large, racial/ethnically diverse cohorts of males and females, and, if feasible, address changes in SSB consumption over time.
Obesity is associated with metabolic perturbations including liver and adipose tissue inflammation, insulin resistance, and type 2 diabetes. Omega-6 fatty acids (ω6) promote and omega-3 fatty acids ...(ω3) reduce inflammation as they can be metabolized to pro- and anti-inflammatory eicosanoids, respectively. 12/15-lipoxygenase (12/15-LO) enzymatically produces some of these metabolites and is induced by high fat (HF) diet. We investigated the effects of altering dietary ω6/ω3 ratio and 12/15-LO deficiency on HF diet-induced tissue inflammation and insulin resistance. We examined how these conditions affect circulating concentrations of oxidized metabolites of ω6 arachidonic and linoleic acids and innate and adaptive immune system activity in the liver. For 15 weeks, wild-type (WT) mice were fed either a soybean oil-enriched HF diet with high dietary ω6/ω3 ratio (11∶1, HFH), similar to Western-style diet, or a fat Kcal-matched, fish oil-enriched HF diet with a low dietary ω6/ω3 ratio of 2.7∶1 (HFL). Importantly, the total saturated, monounsaturated and polyunsaturated fat content was matched in the two HF diets, which is unlike most published fish oil studies in mice. Despite modestly increased food intake, WT mice fed HFL were protected from HFH-diet induced steatohepatitis, evidenced by decreased hepatic mRNA expression of pro-inflammatory genes and genes involved in lymphocyte homing, and reduced deposition of hepatic triglyceride. Furthermore, oxidized metabolites of ω6 arachidonic acid were decreased in the plasma of WT HFL compared to WT HFH-fed mice. 12/15-LO knockout (KO) mice were also protected from HFH-induced fatty liver and elevated mRNA markers of inflammation and lymphocyte homing. 12/15-LOKO mice were protected from HFH-induced insulin resistance but reducing dietary ω6/ω3 ratio in WT mice did not ameliorate insulin resistance or adipose tissue inflammation. In conclusion, lowering dietary ω6/ω3 ratio in HF diet significantly reduces steatohepatitis.
PDF
