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Different effects of high-protein/low-carbohydrate versus standard hypocaloric diet on insulin resistance and lipid profile: role of rs16147 variant of neuropeptide Y.
Antonio de Luis D, Izaola O, Primo D, Aller R.
Diabetes Res Clin Pract. 2019 Aug 23:107825. doi: 10.1016/j.diabres.2019.107825. [Epub ahead of print]
PMID: 31449874
Abstract
BACKGROUND AND AIMS:
Few studies have assessed the effect of the NPY gene rs16147 variant on metabolic response following a dietary intervention. We evaluated the effect of rs16147 on body weight and biochemical changes after a high-protein/low-carbohydrate hypocaloric diet compared with a standard severe hypocaloric diet over 9 months.
MATERIALS AND METHODS:
A population of 270 obese individuals was enrolled. At baseline, participants were randomly allocated to one of two hypocaloric diets, high protein (Diet HP) or standard (Diet S), for a period of 9 months.
RESULTS:
After both diets, all genotypes showed decreased body mass index, weight, fat mass, waist circumference, and leptin levels. Participants with the minor allele (A) assigned to the HP diet showed decreases in total cholesterol (-6.5 ± 4.8 vs 10.1 ± 4.1 mg/dL; p < 0.05), LDL cholesterol (-5.9 ± 3.8 vs 9.6 ± 2.4 mg/dL; p < 0.05), triglycerides (-1.0 ± 4.8 vs 16.2 ± 4.1 mg/dL; p < 0.05), insulin (-0.5 ± 2.8 vs 1.7 ± 2.1 UI/L; p < 0.05), HOMA-IR (-0.2 ± 2.1 vs 0.5 ± 2.0 units; p < 0.05), and CRP (-0.3 ± 0.4 vs 1.3 ± 0.2 mg/dL; p < 0.05). Participants with the minor allele assigned to diet S also showed decreases in total cholesterol (-6.1 ± 4.1 vs 14.4 ± 3.1 mg/dL; p < 0.05), LDL-cholesterol (-3.1 ± 2.8 vs 15.0 ± 3.1 mg/dL; p < 0.05), triglycerides (-6.9 ± 4.1 vs 13.2 ± 4.0 mg/dL; p < 0.05), insulin (-0.3 ± 2.1 vs. -1.2 ± 0.2 UI/L: p < 0.05), HOMA-IR (-0.3 ± 2.1 vs. -1.6 ± 1.1 units: p < 0.05), and CRP (-0.4 ± 0.1 vs 1.1 ± 0.2 mg/dL; p < 0.05).
CONCLUSION:
In obese Caucasians, the presence of the A allele of the rs16147 genetic variant produces a better metabolic response that is secondary to weight loss with two different hypocaloric diets.
KEYWORDS:
NPY gene; SNP; hypocaloric diet; rs16147

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Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, Stadler JT, Pendl T, Prietl B, Url J, Schroeder S, Tadic J, Eisenberg T, Magnes C, Stumpe M, Zuegner E, Bordag N, Riedl R, Schmidt A, Kolesnik E, Verheyen N, Springer A, Madl T, Sinner F, de Cabo R, Kroemer G, Obermayer-Pietsch B, Dengjel J, Sourij H, Pieber TR, Madeo F.
Cell Metab. 2019 Aug 20. pii: S1550-4131(19)30429-2. doi: 10.1016/j.cmet.2019.07.016. [Epub ahead of print]
PMID: 31471173
Abstract
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
KEYWORDS:
RCT; aging; body shape; caloric restriction; cardiovascular disease risk; clinical trial; fasting; fat distribution; intermittent fasting; triiodothyronine

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Time-restricted feeding plus resistance training in active females: a randomized trial.
Tinsley GM, Moore ML, Graybeal AJ, Paoli A, Kim Y, Gonzales JU, Harry JR, VanDusseldorp TA, Kennedy DN, Cruz MR.
Am J Clin Nutr. 2019 Jul 3. pii: nqz126. doi: 10.1093/ajcn/nqz126. [Epub ahead of print]
PMID: 31268131
Abstract
BACKGROUND:
A very limited amount of research has examined intermittent fasting (IF) programs, such as time-restricted feeding (TRF), in active populations.
OBJECTIVE:
Our objective was to examine the effects of TRF, with or without β-hydroxy β-methylbutyrate (HMB) supplementation, during resistance training (RT).
METHODS:
This study employed a randomized, placebo-controlled, reduced factorial design and was double-blind with respect to supplementation in TRF groups. Resistance-trained females were randomly assigned to a control diet (CD), TRF, or TRF plus 3 g/d HMB (TRFHMB). TRF groups consumed all calories between 1200 h and 2000 h, whereas the CD group ate regularly from breakfast until the end of the day. All groups completed 8 wk of supervised RT and consumed supplemental whey protein. Body composition, muscular performance, dietary intake, physical activity, and physiological variables were assessed. Data were analyzed prior to unblinding using mixed models and both intention-to-treat (ITT) and per protocol (PP) frameworks.
RESULTS:
Forty participants were included in ITT, and 24 were included in PP. Energy and protein intake (1.6 g/kg/d) did not differ between groups despite different feeding durations (TRF and TRFHMB: ∼7.5 h/d; CD: ∼13 h/d). Comparable fat-free mass (FFM) accretion (+2% to 3% relative to baseline) and skeletal muscle hypertrophy occurred in all groups. Differential effects on fat mass (CD: +2%; TRF: -2% to -4%; TRFHMB: -4% to -7%) were statistically significant in the PP analysis, but not ITT. Muscular performance improved without differences between groups. No changes in physiological variables occurred in any group, and minimal side effects were reported.
CONCLUSIONS:
IF, in the form of TRF, did not attenuate RT adaptations in resistance-trained females. Similar FFM accretion, skeletal muscle hypertrophy, and muscular performance improvements can be achieved with dramatically different feeding programs that contain similar energy and protein content during RT. Supplemental HMB during fasting periods of TRF did not definitively improve outcomes.
KEYWORDS:
body composition; energy restriction; fat loss; intermittent energy restriction; intermittent fasting; muscle mass; muscular strength; protein; resistance exercise; weight training

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Effects of caloric restriction on the expression of lipocalin-2 and its receptor in the brown adipose tissue of high-fat diet-fed mice.
Park KA, Jin Z, An HS, Lee JY, Jeong EA, Choi EB, Kim KE, Shin HJ, Lee JE, Roh GS.
Korean J Physiol Pharmacol. 2019 Sep;23(5):335-344. doi: 10.4196/kjpp.2019.23.5.335. Epub 2019 Aug 26.
PMID: 31496871
https://synapse.koreamed.org/Synapse/Data/PDFData/0067KJPP/kjpp-23-335.pdf
Abstract
Obesity causes inflammation and impairs thermogenic functions in brown adipose tissue (BAT). The adipokine lipocalin 2 (LCN2) has been implicated in inflammation and obesity. Herein, we investigated the protective effects of caloric restriction (CR) on LCN2-mediated inflammation and oxidative stress in the BAT of high-fat diet (HFD)-fed mice. Mice were fed a HFD for 20 weeks and then either continued on the HFD or subjected to CR for the next 12 weeks. CR led to the browning of the white fat-like phenotype in HFD-fed mice. Increased expressions of LCN2 and its receptor in the BAT of HFD-fed mice were significantly attenuated by CR. Additionally, HFD+CR-fed mice had fewer neutrophils and macrophages expressing LCN2 and iron-positive cells than HFD-fed mice. Further, oxidative stress and mitochondrial fission induced by a HFD were also significantly attenuated by CR. Our findings indicate that the protective effects of CR on inflammation and oxidative stress in the BAT of obese mice may be associated with regulation of LCN2.
KEYWORDS:
Brown adipose tissue; Caloric restriction; Lipocalin 2; Obesity

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Exercise degrades Bone in Caloric Restriction, despite Suppression of Marrow Adipose Tissue (MAT).
McGrath C, Sankaran JS, Misaghian-Xanthos N, Sen B, Xie Z, Styner MA, Zong X, Rubin J, Styner M.
J Bone Miner Res. 2019 Sep 11. doi: 10.1002/jbmr.3872. [Epub ahead of print]
PMID: 31509274
Abstract
Marrow adipose tissue (MAT) and its relevance to skeletal health during caloric restriction (CR) is unknown: it remains unclear whether exercise, which is anabolic to bone in a calorie-replete state, alters bone or MAT in CR. We hypothesized that response of bone and MAT to exercise in CR differs from the calorie-replete state. Ten-week-old female B6 mice fed a regular (RD) or 30% CR-diet were allocated to sedentary (RD CR, n = 10/group) or running exercise (RD-E, CR-E, n = 7/group). After 6 weeks, CR mice weighed 20% less than RD, p < 0.001; exercise did not affect weight. Femoral bone volume (BV) via 3D MRI was 20% lower in CR vs. RD (p < 0.0001). CR was associated with decreased bone by μCT: Tb. Th was 16% less in CR vs. RD, p < 0.003, Ct.Th was 5% less, p < 0.07. In CR-E Tb.Th was 40% less than RD-E, p < 0.0001. Exercise increased Tb.Th in RD (+23% RD-E vs. RD p < 0.003) but failed to do so in CR. Cortical porosity increased after exercise in CR (+28%, p = 0.04), suggesting exercise during CR is deleterious to bone. In terms of bone fat, metaphyseal MAT/ BV rose 159% in CR vs. RD, p = 0.003 via 3D MRI. Exercise decreased MAT/ BV by 52% in RD, p < 0.05 and also suppressed MAT in CR (-121%, p = 0.047). Histomorphometric analysis of adipocyte area correlated with MAT by MRI (R2  = 0.6233, p < 0.0001). With respect to bone, TRAP and Sost mRNA were reduced in CR. Intriguingly, the repressed Sost in CR rose with exercise and may underlie the failure of CR-bone quantity to increase in response to exercise. Notably, CD36, a marker of fatty acid uptake, rose 4088% in CR (p < 0.01 vs. RD) suggesting that basal increases in MAT during calorie restriction serve to supply local energy needs, and are depleted during exercise with a negative impact on bone. This article is protected by copyright. All rights reserved.
KEYWORDS:
Bone-fat interactions; Exercise; Marrow Adipose Tissue (MAT)

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This post today of Al's ("Exercise degrades Bone in Calorie Restriction") is very concerning. I'm assuming similar effects accrue to humans. The previous concerns among CR practitioners, if I recall correctly, were that CR could cause bone fragility. That exercise doesn't counterbalance the effect but instead makes matters worse is an even greater concern.

Informed comments and relevant research would be appreciated.

Edited by ras

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Dietary restriction in ILSXISS mice is associated with widespread changes in splicing regulatory factor expression levels.
Lee BP, Mulvey L, Barr G, Garratt J, Goodman E, Selman C, Harries LW.
Exp Gerontol. 2019 Sep 12:110736. doi: 10.1016/j.exger.2019.110736. [Epub ahead of print]
PMID: 3152172
Abstract
Dietary restriction (DR) represents one of the most reproducible interventions to extend lifespan and improve health outcomes in a wide range of species, but substantial variability in DR response has been observed, both between and within species. The mechanisms underlying this variation in effect are still not well characterised. Splicing regulatory factors have been implicated in the pathways linked with DR-induced longevity in C. elegans and are associated with lifespan itself in mice and humans. We used qRT-PCR to measure the expression levels of a panel of 20 age- and lifespan-associated splicing regulatory factors in brain, heart and kidney derived from three recombinant inbred strains of mice with variable lifespan responses to short-term (2 months) or long-term (10 months) 40% DR to determine their relationship to DR-induced longevity. We identified 3 patterns of association; i) splicing factors associated with DR alone, ii) splicing factors associated with strain alone or iii) splicing factors associated with both DR and strain. Tissue specific variation was noted in response to short term or long-term DR, with the majority of effects noted in brain following long term DR in the positive responder strain TejJ89. Association in heart and kidney were less evident, and occurred following short term DR. Splicing factors associated with both DR and strain may be mechanistically involved in strain-specific differences in response to DR. We provide here evidence concordant with a role for some splicing factors in the lifespan modulatory effects of DR across different mouse strains and in different tissues.
KEYWORDS:
Dietary restriction; Splicing factors

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Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension.
Yu D, Tomasiewicz JL, Yang SE, Miller BR, Wakai MH, Sherman DS, Cummings NE, Baar EL, Brinkman JA, Syed FA, Lamming DW.
Cell Rep. 2019 Oct 1;29(1):236-248.e3. doi: 10.1016/j.celrep.2019.08.084.
PMID: 31577953
https://www.cell.com/cell-reports/pdf/S2211-1247(19)31146-5.pdf
Abstract
Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic target of rapamycin complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.
KEYWORDS:
Rictor; adipose; calorie restriction; fitness; frailty; healthspan; insulin sensitivity; lifespan; lipogenesis; mTORC2

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Dietary restriction regimens for fighting kidney disease: Insights from rodent studies.
Singh G, Krishan P.
Exp Gerontol. 2019 Oct 5:110738. doi: 10.1016/j.exger.2019.110738. [Epub ahead of print] Review.
PMID: 31593758
Abstract
This review critically discusses the research findings on the effects of various dietary restriction regimens in rodent models of kidney disease. Long-term caloric restriction executed at both early and progressive stages of kidney disease was found to exert beneficial effects in rodents. Moreover, some studies have also demonstrated the efficacy of short-term caloric restriction in treating the kidney disease of variable aetiologies possibly by improving mitochondrial dysfunction, autophagy process and suppression of inflammation. However, the mechanisms underlying these short-term caloric restriction mediated protective effects in rodent models of kidney disease are not completely understood. Importantly, few available evidences have also suggested that carbohydrate restriction can exert beneficial effects in aging and experimentally induced renal injury models, but the mechanisms are not explored yet. Interestingly, the benefits of low protein diet in kidney disease models are extensively reported in literature. However, in most of these studies implementation of the low protein dietary regimen was found to associated with increased high carbohydrate and caloric intake (non-isocaloric). Thus, testing the effects of low protein diet under isocaloric conditions might further help to particularly understand the role of dietary protein content in pathology of kidney disease. Moreover, the direct evidences comparing the efficacy of various dietary restriction regimens in rodent models of kidney diseases are also scarce at present.
KEYWORDS:
Aging kidney disease; Autophagy; Carbohydrate restriction; Chronic renal failure; Diabetic nephropathy; Diet restriction; Low protein diet; Polycystic kidney disease

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Impact of energy turnover on fat balance in healthy young men during energy balance, caloric restriction and overfeeding.
Nas A, Büsing F, Hägele FA, Hasler M, Müller MJ, Bosy-Westphal A.
Br J Nutr. 2019 Oct 11:1-27. doi: 10.1017/S0007114519002551. [Epub ahead of print]
PMID: 31601285
Abstract
Body weight control is thought to be improved when physical activity and energy intake are both high (high energy turnover). The aim of this study was to investigate the short-term impact of energy turnover (ET) on fat balance during zero energy balance, caloric restriction and overfeeding. In a randomized crossover study, 9 healthy men (BMI: 23.0 ±2.1 kg/m2, 26.6 ±3.5 y) passed 3x3 days in a metabolic chamber: 3 levels of ET (low, medium and high; physical activity level = 1.3-1.4, 1.5-1.6 and 1.7-1.8) were performed at zero energy balance (EB), caloric restriction (CR), and overfeeding (OF) (100%, 75%, 125% of individual energy requirement). Different levels of ET were obtained by walking (4 km/h) on a treadmill (0, 165, 330 min). 24-h macronutrient oxidation and relative macronutrient balance (oxidation relative to intake) were calculated and free fatty acids, 24-h insulin and catecholamine secretion were analyzed as determinants of fat oxidation. During EB and OF, 24-h fat oxidation increased with higher ET. This resulted in a higher relative fat balance at medium ET (EB: +17%, OF: +14%) and high ET (EB: +23%, OF: +17%) compared to low ET (all p<0.05). In contrast, CR led to a stimulation of 24-h fat oxidation irrespective of ET (no differences in relative fat balance between ET levels, p>0.05). In conclusion, under highly controlled conditions a higher energy turnover improved relative fat balance in young healthy men during overfeeding and energy balance compared to a sedentary state.
KEYWORDS:
ClinicalTrials.gov as NCT03361566; energy expenditure; energy turnover; fat oxidation; metabolic chamber; physical activity

The Effectiveness of Intermittent Fasting to Reduce Body Mass Index and Glucose Metabolism: A Systematic Review and Meta-Analysis.
Cho Y, Hong N, Kim KW, Cho SJ, Lee M, Lee YH, Lee YH, Kang ES, Cha BS, Lee BW.
J Clin Med. 2019 Oct 9;8(10). pii: E1645. doi: 10.3390/jcm8101645.
PMID: 31601019
https://www.mdpi.com/2077-0383/8/10/1645/htm
Abstract
The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, -0.75 kg/m2; 95% CI, -1.44 to -0.06), fasting glucose level (WMD, -4.16 mg/dL; 95% CI, -6.92 to -1.40), and homeostatic model assessment of insulin resistance (WMD, -0.54; 95% CI, -1.05 to -0.03). Fat mass (WMD, -0.98 kg; 95% CI, -2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL; 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, -0.51 ng/mL; 95% CI, -0.77 to -0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.
KEYWORDS:
body mass index; glucose metabolism; insulin resistance; intermittent fasting

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