Contributions of upper gut hormones and motility to the energy intake-suppressant effects of intraduodenal nutrients in healthy, lean men - a pooled-data analysis

Accepted: 8 August 2016We have previously identified pyloric pressures and plasma cholecystokinin (CCK) concentrations as independent determinants of energy intake following administration of intraduodenal lipid and intravenous CCK. We evaluated in healthy men whether these parameters also determine energy intake in response to intraduodenal protein, and whether, across the nutrients, any predominant gastrointestinal (GI) factors exist, or many factors make small contributions. Data from nine published studies, in which antropyloroduodenal pressures, GI hormones, and GI /appetite perceptions were measured during intraduodenal lipid or protein infusions, were pooled. In all studies energy intake was quantified immediately after the infusions. Specific variables for inclusion in a mixed-effects multivariable model for determination of independent predictors of energy intake were chosen following assessment for collinearity, and within-subject correlations between energy intake and these variables were determined using bivariate analyses adjusted for repeated measures. In models based on all studies, or lipid studies, there were significant effects for amplitude of antral pressure waves, premeal glucagon-like peptide-1 (GLP-1) and time-to-peak GLP-1 concentrations, GLP-1 AUC and bloating scores (P < 0.05), and trends for basal pyloric pressure (BPP), amplitude of duodenal pressure waves, peak CCK concentrations, and hunger and nausea scores (0.05 < P ≤ 0.094), to be independent determinants of subsequent energy intake. In the model including the protein studies, only BPP was identified as an independent determinant of energy intake (P < 0.05). No single parameter was identified across all models, and effects of the variables identified were relatively small. Taken together, while GI mechanisms contribute to the regulation of acute energy intake by lipid and protein, their contribution to the latter is much less. Moreover, the effects are likely to reflect small, cumulative contributions from a range of interrelated factors.Gudrun Schober, Kylie Lange, Robert E. Steinert, Amy T. Hutchison, Natalie D. Luscombe-Marsh, Maria F. Landrock, Michael Horowitz, Radhika V. Seimon and Christine Feinle-Bisse

Intermittent fasting increases energy expenditure and promotes adipose tissue browning in mice

Objective: Intermittent fasting (IF) may limit metabolic adaptations that reduce energy expenditure, potentially by stimulating white adipose tissue (WAT) browning. The aim of this study was to examine the effects of 8 wk of IF on energy metabolism and markers of WAT browning in lean and diet-induced obese mice and in women who were overweight or obese. Methods: Male C57 BL/6 J mice were fed chow or a high-fat diet (HFD; 43%) for 8 wk before undergoing IF (3 non-consecutive d/wk) for an additional 8 wk. Food intake, energy expenditure, and inguinal and gonadal fat pads were collected in fed or fasted conditions (22 h, IF mice only). Subcutaneous adipose tissue (SAT) was also collected at baseline, and after 8 wk of IF (in the fed state, and after a 24-h fast), in women with overweight or obesity. Uncoupling protein 1 (UCP1) was assessed by quantitative real-time polymerase chain reaction (mice and humans) and immunohistochemistry (mice). Results: IF reduced body weight and energy intake in HFD fed mice and reduced gonadal and inguinal fat pad weights in both diet groups. IF increased energy expenditure, meal number, Ucp1 mRNA levels in inguinal and gonadal fat depots, and UCP1 protein in inguinal fat in both diet groups on fed days. In women, IF reduced body weight and fat mass, but did not alter UCP1mRNA levels. Conclusions: IF increased energy expenditure and promoted WAT browning in mice but did not alter UCP1 mRNA levels in SAT in women.Bo Liu, Amanda J. Page, Amy T. Hutchison, Gary A. Wittert, Leonie K. Heilbron

Adipose tissue remodeling following eight-week calorie restriction or intermittent fasting in females who are overweight and obese

AbstractBo Liu, Amy T. Hutchison, Campbell H. Thompson, Gary A. Wittert, Leonie Heilbron

The Break-Fast study protocol: a single arm pre-post study to measure the effect of a protein-rich breakfast on autophagic flux in fasting healthy individuals

Published online: 01 November 2022Background: Autophagy is a cellular process that cleanses cells and is particularly important during ageing. Autophagy has been extensively studied in vitro and in animal models and is known to be sensitive to nutrition. However, human data are limited because autophagic flux (autophagic degradative activity) has been challenging to measure in humans. This protocol paper describes the Break-Fast study, in which autophagic flux will be measured using a recently developed blood test, before and after ingestion of whey protein. This aims to determine whether an acute nutritional intervention can change autophagy in humans. Methods: A minimum of forty healthy participants (both male and female) aged 20–50 years, BMI 18.5–29.9 kg/m2 will be recruited into this single arm pre-post study. Participants will visit the clinic after an overnight fast for a first blood collection after which they will consume a whey protein-rich drink. A second blood collection will be performed 60 minutes after consumption of the drink. The primary outcome is the change in autophagic flux at 60 minutes post drink. Secondary outcomes include changes in blood glucose, autophagy-related proteins and mRNA, plasma hormones (e.g. insulin, C-peptide, adiponectin, GLP-1, GIP, ghrelin), cytokines, amino acids and lipids, protein synthesis, and correlation between molecular cell damage and autophagic flux. Discussion: This study will provide information about whether autophagy responds to nutrients in humans, and if nutritional strategies could be used to treat or prevent autophagy-related diseases such as Alzheimer’s disease or cancer. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), anzctr. org. au ACTRN12621001029886. Registered on 5 August 2021.Julien Bensalem, Leonie K. Heilbronn, Jemima R. Gore, Amy T. Hutchison, Timothy J. Sargeant and Célia Fourrie

Effects of intermittent fasting or calorie restriction on markers of lipid metabolism in human skeletal muscle

Context: Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR). Objective: In a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle. Design: Seventy-six women (BMI 25-40 kg/m²) were randomized to one of three diets for eight weeks and provided with foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast, prior to a 24-hour fast on 3 non-consecutive days per week. On non-fasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, non-esterified fatty acids (NEFA), β-hydroxybutyrate, and markers of lipid metabolism and oxidative stress in muscle by qPCR were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups). Results: IF70 resulted in greater weight and fat losses and reduced NEFA versus CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes GPX1, SOD1 and SOD2 versus CR70. Fasting for 24-hours increased NEFA and β-hydroxybutyrate in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels. Conclusoins: In comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.Bo Liu, Amy T. Hutchison, Campbell H. Thompson, Kylie Lange, Gary A. Wittert, and Leonie K. Heilbron

Intermittent fasting increases growth differentiation factor 15 in females with overweight or obesity but not associated with food intake

Available online 9 December 2022Growth differentiation factor 15 (GDF15) increases with acute fast in animals, and high GDF15 reduces food intake in rodents. We explored whether GDF15 was altered following intermittent fasting (IF) versus caloric restriction (CR), and associations with energy intake. Females with obesity received all foods at 70% (IF70 and CR70) or 100% of energy requirements for 8 weeks. IF ate 2–9% less than provided on refeeding days, resulting in greater weight losses. GDF15 was increased 5% more in IF70 versus CR70, but not associated with energy intake. This rise in GDF15 is unlikely to explain restriction of energy intake during IF.Kai Liu, Bo Liu, Gary A. Wittert, Campbell H. Thompson, Amy T. Hutchison, Leonie K. Heilbron

Time-restricted feeding improves glucose tolerance in men at risk for type 2 diabetes: a randomized crossover trial

Objective: This study aimed to assess the effects of 9-hour time-restricted feeding (TRF), early (TRFe) or delayed (TRFd), on glucose tolerance in men at risk for type 2 diabetes. Methods: Fifteen men (age 55 ± 3 years, BMI 33.9 ± 0.8 kg/m² ) wore a continuous glucose monitor for 7 days of baseline assessment and during two 7-day TRF conditions. Participants were randomized to TRFe (8 am to 5 pm) or TRFd (12 pm to 9 pm), separated by a 2-week washout phase. Glucose, insulin, triglycerides, nonesterified fatty acids, and gastrointestinal hormone incremental areas under the curve were calculated following a standard meal on days 0 and 7 at 8 am (TRFe) or 12 pm (TRFd). Results: TRF improved glucose tolerance as assessed by a reduction in glucose incremental area under the curve (P = 0.001) and fasting triglycerides (P = 0.003) on day 7 versus day 0. However, there were no mealtime by TRF interactions in any of the variables examined. There was also no effect of TRF on fasting and postprandial insulin, nonesterified fatty acids, or gastrointestinal hormones. Mean fasting glucose by continuous glucose monitor was lower in TRFe (P = 0.02) but not TRFd (P = 0.17) versus baseline, but there was no difference between TRF conditions. Conclusions: While only TRFe lowered mean fasting glucose, TRF improved glycemic responses to a test meal in men at risk for type 2 diabetes regardless of the clock time that TRF was initiated.Amy T. Hutchison, Prashant Regmi, Emily N.C. Manoogian, Jason G. Fleischer, Gary A. Wittert, Satchidananda Panda, and Leonie K. Heilbron

Eight weeks of intermittent fasting versus calorie restriction does not alter eating behaviors, mood, sleep quality, quality of life and cognitive performance in women with overweight

Human trials that compare intermittent fasting (IF) to calorie restriction (CR) with psychological, behavioral and cognition outcomes are limited. We hypothesized that there would be no difference between CR and IF on perceived eating behaviors, mood, sleep quality, quality of life (QOL) and cognition in women with overweight and obesity. In this prespecified secondary analysis of an open-label, single center, parallel assignment, randomized controlled trial, healthy women with overweight or obesity (N = 46, mean [SD] age 50 [9] years, BMI 32.9 [4.4] kg/m2), without a diagnosed eating disorder and who were randomized into 2 weight loss groups (prescribed 70% of calculated energy requirements as IF or CR) were included. Measurements were assessed in both IF and CR groups following a 12-hour overnight fast during baseline and week 8 and additionally following a 24-hour fast in the IF group only at week 8. We observed that IF produced greater weight and body fat loss than CR (P .05). IF may be a viable alternative to CR for weight loss, in the short-term, without adversely impacting eating behaviors, mood, sleep quality, QOL or cognition in healthy women with overweight or obesity. However, larger and long term trials are required.Xiao TongTeong, Amy T.Hutchison, Bo Liu, Gary A.Wittert, Kylie Lange, Siobhan Banks, Leonie K.Heilbron

Intermittent fasting does not uniformly impact genes involved in circadian regulation in women with obesity

Published online 21 May 2020Objective: This study aimed to examine the effects of intermittent fasting (IF) on mRNA levels of peripheral clock genes in skeletal muscle and subcutaneous adipose tissue (SAT) in women with obesity. Methods: Women were randomized to one of two IF protocols and pro-vided with all foods at 100% or 70% of calculated weekly energy require-ments for 8 weeks. Breakfast was consumed before a 24-hour fast, which was initiated on three nonconsecutive days per week. Muscle and SAT biopsies were performed at 8 AM after an overnight fast at baseline and at week 8 on a refed day and again following a 24-hour fast at week 8 for analysis of the mRNA levels of key genes involved in circadian regulation. Results: A group-by-time interaction was observed in Per2 in muscle (F = 3.497, P = 0.044) and SAT (F = 6.686, P = 0.008), but significance was lost upon post hoc adjustment. A time effect was observed in Rora in muscle, which was decreased by refeeding in both groups (F = 7.225, P = 0.003). Conclusions: There was no universal effect of IF to alter peripheral clocks, which may be partly because of the alignment of the fasting/feeding cycle with the biological clock. Optimizing intermittent fasting protocols could be important to prevent circadian misalignment in humans.Lijun Zhao, Amy T. Hutchison, Gary A. Wittert, Campbell H. Thompson, Kylie Lange, Bo Liu, Leonie K. Heilbron

Intermittent fasting activates markers of autophagy in mouse liver, but not muscle from mouse or humans

Objectives: Intermittent fasting (IF) activates autophagy in cardiac muscle and pancreatic islets. We examined the effect of IF on markers of autophagy in liver and skeletal muscle in mice and in humans. Methods: Ten-wk-old C57 BL/6 J male mice were ad libitum (AL) fed a high-fat diet (HFD) or chow diet for 8 wk, before randomization to AL or IF (24-h fast, 3 non-consecutive days per week) for 8 wk (8–16 per group). Tissue was collected in the fed or 22-h fasted state. Fifty women (51 ± 2 y, 31.8 ± 4.3 kg/m2) were randomly assigned to one of two IF protocols (24-hfast, 3 non-consecutive days per week) and fed at 70% (IF70) or 100% (IF100) of energy requirements for 8 wk. Vastus lateralis muscle was collected at 0800 after 12- and 24-h fasts. Microtubule-associated protein light chain 1 (Map1 lc3 b), Beclin1 (Becn1), Sequestosome 1 (Sqstm1/p62), and Lysosomal associated membrane protein 2 (Lamp2) were assessed by quantitative polymerase chain reaction and LC3, BECLIN1 and LAMP1 protein content by immunoblotting. Results: Fasting increased hepatic LC3 I protein and Map1 lc3 b mRNA levels in IF mice fed chow or HFD. LAMP1 protein and Beclin1 mRNA levels in liver were also increased by fasting, but only in chow-fed mice. IF did not activate markers of autophagy in mouse muscle. In humans, a 24-h fast increased SQSTM1. BECLIN1, SQSTM1 and LAMP2 mRNA levels were decreased in IF70 after a 12-h overnight fast . Conclusion: Markers of autophagy in liver, but not in muscle, were elevated in response to IF in mice. In humans, autophagy markers in muscle were reduced, likely in response to weight loss.Rajesh Chaudhary, Bo Liu, Julien Bensalem, Timothy J. Sargeant, Amanda J. Page, Gary A. Wittert, Amy T. Hutchison, Leonie K. Heilbron