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New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.
Flanagan, EW, Spann, R, Berry, SE, Berthoud, HR, Broyles, S, Foster, GD, Krakoff, J, Loos, RJF, Lowe, MR, Ostendorf, DM, et al
Obesity (Silver Spring, Md.). 2023;(12):2895-2908
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Abstract
Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.
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Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study.
Das, JK, Banskota, N, Candia, J, Griswold, ME, Orenduff, M, de Cabo, R, Corcoran, DL, Das, SK, De, S, Huffman, KM, et al
Aging cell. 2023;22(12):e13963
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Plain language summary
Reducing calorie intake by 12% has been shown in one randomised control trial (RCT) called the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, to result in both fat and muscle loss but without any changes to muscle strength and function. The present study aimed to take 90 of the individuals from the original CALERIE study to understand the mechanisms behind this. The results showed that after 12 months individuals who were given a calorie reduced diet lost significant amounts of weight compared to control and this loss was maintained after 2 years. This included muscle loss, but despite this, there was no change in muscle strength of individuals on calorie reduced diet. Genetic analysis showed that genes are involved in muscle quality and anti-ageing. It was concluded that 2 years of calorie restriction resulted in both fat and muscle loss but did not compromise muscle function. The upregulation of genes involved in muscle quality and anti-ageing may be responsible for this.
Expert Review
Conflicts of interest:
None
Take Home Message:
- CR can aid weight loss and sustain losses long-term. Some lean muscle loss may also be seen, but this does not mean that muscle function has been compromised
- CR can trigger molecular and cellular mechanisms involved in skeletal muscle, sustaining functionality during a weight loss programme.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) randomised control trial (RCT) showed that 12% caloric restriction (CR) induced muscle loss, without compromising muscle strength. This analysis of 90 individuals from that study aimed to determine the mechanisms behind this.
Methods
- The CALERIE study was an RCT that assessed the effects of 25% CR over 2 years compared to an ad libitum control group
- This study ran alongside the CALERIE study and took skeletal muscle biopsies from a subset of 90 individuals at baseline, 12 months, and 24 months from the CR group and ad libitum control group
- This yielded 162 muscle biopsies over 2 years
- Skeletal muscle was taken from the vastus lateralis muscle and lean leg mass, and muscle strength were assessed
- In addition, RNA was extracted, and gene expression assessed.
Results
- Participants on CR lost significant amounts of weight (P=<0.001) at 12 months, with no further improvements at 2 years. Quantity or range of weight loss data was not provided
- Control participants maintained their weight over 2 years
- There were no changes in muscle strength in CR individuals despite a significant loss of muscle mass (no P value given)
- Although adjustments for change in lean leg mass resulted in less of a decline in the isokinetic muscle strength test compared to control (average power P=0.0058 and peak torque P=0.0144)
- RNA analysis showed 797 genes were overexpressed and 206 underexpressed in CR compared to control
- CR was associated with enhanced anti-ageing mechanisms with genes such as those involved in androgen receptor signalling, autophagy, circadian rhythms, DNA repair, FOXO mediated transcription, and mitochondrial biogenesis all upregulated and inflammatory genes downregulated
- These changes were responsible for the positive effect on muscle quality in individuals in the CR group.
Conclusion
- It was concluded that 2 years of CR preserved muscle function despite muscle mass loss, through upregulation of the genes involved in muscle quality and anti-ageing.
Clinical practice applications:
- Healthcare professionals may consider a 12% CR diet for individuals who would like to lose weight and maintain its loss long-term, without compromising muscle function
- Although lean muscle mass may be lost, muscle function should not be affected, but should be monitored to ensure functionality.
Considerations for future research:
- The possible effects of combining CR with muscle strength exercises should be considered for future research to determine if muscle mass loss is prevented and whether this impacts further fat loss.
Abstract
The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high-depth RNA-Seq (387-618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12- and 24-month follow-up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein-coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.
Tobias, DK, Merino, J, Ahmad, A, Aiken, C, Benham, JL, Bodhini, D, Clark, AL, Colclough, K, Corcoy, R, Cromer, SJ, et al
Nature medicine. 2023;(10):2438-2457
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Abstract
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial.
Huffman, KM, Parker, DC, Bhapkar, M, Racette, SB, Martin, CK, Redman, LM, Das, SK, Connelly, MA, Pieper, CF, Orenduff, M, et al
EClinicalMedicine. 2022;:101261
Abstract
BACKGROUND For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values within ranges considered normal for healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young (21-50 years), normal weight healthy population undergoing calorie restriction for two years. METHODS The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, multicenter, randomized controlled trial (May 2007-November 2012) in healthy, adults without obesity to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9 ± 7.2 years and body mass index (BMI) 25.1 ± 1.7 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy. FINDINGS Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes-Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and low-density lipoprotein particles, a shift to larger high-density lipoprotein particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women. INTERPRETATION In normal to slightly overweight adults without overt risk factors or disease, 12 months of ∼12% CR improved newly identified risk markers for atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These markers suggest that CR improves risks by reducing inflammation and BCAAs and shifting lipoproteins from atherogenic to cholesterol transporting. Additionally, these improvements are greater for men and for those with greater BMIs indicating sex and BMI-influences merit attention in future investigations of lifestyle-mediated improvements in disease risk factors. FUNDING The CALERIE™ trial design and implementation were supported by a National Institutes of Health (NIH) U-grant provided to four institutions, the three intervention sites and a coordinating center (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480). For this secondary analysis including sample acquisition and processing, data analysis and interpretation, additional funding was provided by the NIH to authors as follows: R01 AG054840 (MO, VBK); R33 AG070455 (KMH, DCP, MB, SBR, CKM, LMR, SKD, CFP, CJR, WEK); P30 DK072476 (CKM, LMR); and U54 GM104940 (CKM, LMR).
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Lifestyle interventions in pregnancy targeting GDM prevention: looking ahead to precision medicine.
Sparks, JR, Ghildayal, N, Hivert, MF, Redman, LM
Diabetologia. 2022;(11):1814-1824
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Abstract
Gestational diabetes mellitus (GDM) is the most prevalent pregnancy-related endocrinopathy, affecting up to 25% of pregnancies worldwide. Pregnant individuals who develop GDM have an increased risk of complications during pregnancy and birth, as well as future development of type 2 diabetes mellitus and CVD. This increased risk is subsequently passed along to the offspring, perpetuating a cycle of metabolic dysfunction across generations. GDM prevention strategies have had mixed results for many years, but more recent systematic reviews and meta-analyses have suggested potential new avenues of prevention. The objective of this review is to summarise the literature examining the efficacy of lifestyle interventions for the prevention of GDM and to uncover if specific individual-level characteristics influence this outcome. Based on the present literature, we determined that future trials should be designed to understand if initiation of lifestyle intervention in the preconception period is more effective to reduce GDM. Furthermore, trials initiated during pregnancy should be developed through the lens of precision prevention. That is, trials should tailor intervention approaches based on individual-level risk defined by the presence of modifiable and non-modifiable risk factors. Finally, future interventions might also benefit from just-in-time adaptive intervention designs, which allow for interventions to be modified in real-time based on objective assessments of an individual's response.
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The energy balance model of obesity: beyond calories in, calories out.
Hall, KD, Farooqi, IS, Friedman, JM, Klein, S, Loos, RJF, Mangelsdorf, DJ, O'Rahilly, S, Ravussin, E, Redman, LM, Ryan, DH, et al
The American journal of clinical nutrition. 2022;(5):1243-1254
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Abstract
A recent Perspective article described the "carbohydrate-insulin model (CIM)" of obesity, asserting that it "better reflects knowledge on the biology of weight control" as compared with what was described as the "dominant energy balance model (EBM)," which fails to consider "biological mechanisms that promote weight gain." Unfortunately, the Perspective conflated and confused the principle of energy balance, a law of physics that is agnostic as to obesity mechanisms, with the EBM as a theoretical model of obesity that is firmly based on biology. In doing so, the authors presented a false choice between the CIM and a caricature of the EBM that does not reflect modern obesity science. Here, we present a more accurate description of the EBM where the brain is the primary organ responsible for body weight regulation operating mainly below our conscious awareness via complex endocrine, metabolic, and nervous system signals to control food intake in response to the body's dynamic energy needs as well as environmental influences. We also describe the recent history of the CIM and show how the latest "most comprehensive formulation" abandons a formerly central feature that required fat accumulation in adipose tissue to be the primary driver of positive energy balance. As such, the new CIM can be considered a special case of the more comprehensive EBM but with a narrower focus on diets high in glycemic load as the primary factor responsible for common obesity. We review data from a wide variety of studies that address the validity of each model and demonstrate that the EBM is a more robust theory of obesity than the CIM.
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Predicting energy intake in adults who are dieting and exercising.
Gerving, C, Lasater, R, Starling, J, Ostendorf, DM, Redman, LM, Estabrooks, C, Cummiskey, K, Antonetti, V, Thomas, DM
International journal of obesity (2005). 2022;(12):2095-2101
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BACKGROUND When a lifestyle intervention combines caloric restriction and increased physical activity energy expenditure (PAEE), there are two components of energy balance, energy intake (EI) and physical activity energy expenditure (PAEE), that are routinely misreported and expensive to measure. Energy balance models have successfully predicted EI if PAEE is known. Estimating EI from an energy balance model when PAEE is not known remains an open question. OBJECTIVE The objective was to evaluate the performance of an energy balance differential equation model to predict EI in an intervention that includes both calorie restriction and increases in PAEE. DESIGN The Antonetti energy balance model that predicts body weight trajectories during weight loss was solved and inverted to estimate EI during weight loss. Using data from a calorie restriction study that included interventions with and without prescribed PAEE, we tested the validity of the Antonetti weight predictions against measured weight and the Antonetti EI model against measured EI using the intake-balance method at 168 days. We then evaluated the predicted EI from the model against measured EI in a study that prescribed both calorie restriction and increased PAEE. RESULTS Compared with measured body weight at 168 days, the mean (±SD) model error was 1.30 ± 3.58 kg. Compared with measured EI at 168 days, the mean EI (±SD) model error in the intervention that prescribed calorie restriction and did not prescribe increased PAEE, was -84.9 ± 227.4 kcal/d. In the intervention that prescribed calorie restriction combined with increased PAEE, the mean (±SD) EI model error was -155.70 ± 205.70 kcal/d. CONCLUSION The validity of the newly developed EI model was supported by experimental observations and can be used to determine EI during weight loss.
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An Overview of Obesity, Cholesterol, and Systemic Inflammation in Preeclampsia.
Alston, MC, Redman, LM, Sones, JL
Nutrients. 2022;(10)
Abstract
Preeclampsia (PE), an inflammatory state during pregnancy, is a significant cause of maternal and fetal morbidity and mortality. Adverse outcomes associated with PE include hypertension, proteinuria, uterine/placental abnormalities, fetal growth restriction, and pre-term birth. Women with obesity have an increased risk of developing PE likely due to impaired placental development from altered metabolic homeostasis. Inflammatory cytokines from maternal adipose tissue and circulating cholesterol have been linked to systemic inflammation, hypertension, and other adverse outcomes associated with PE. This review will summarize the current knowledge on the role of nutrients, obesity, and cholesterol signaling in PE with an emphasis on findings from preclinical models.
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Challenges in defining successful adherence to calorie restriction goals in humans: Results from CALERIE™ 2.
Martin, CK, Höchsmann, C, Dorling, JL, Bhapkar, M, Pieper, CF, Racette, SB, Das, SK, Redman, LM, Kraus, WE, Ravussin, E, et al
Experimental gerontology. 2022;:111757
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Abstract
BACKGROUND The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 trial tested the effects of two years of 25% calorie restriction (CR) on aging in humans. CALERIE 2 was one of the first studies to use a graph of predicted weight loss to: 1) provide a proxy of dietary adherence, and 2) promote dietary adherence. Assuming 25% CR, each participant's weight over time was predicted, with upper and lower bounds around predicted weights. Thus, the resulting weight graph included a zone or range of body weights that reflected adherence to 25% CR, and this was named the zone of adherence. Participants were considered adherent if their weight was in this zone. It is unlikely, however, that the entire zone reflects 25% CR. OBJECTIVES To determine the level of CR associated with the zone of adherence and if the level of CR achieved by participants was within the zone. METHODS Percent CR associated with the upper and lower bounds of the zone were determined via the Body Weight Planner (https://www.niddk.nih.gov/bwp) for participants in the CALERIE 2 CR group (N = 143). Percent CR achieved by participants was estimated with the intake-balance method. RESULTS At month 24, the zone of adherence ranged from 10.4(0.0)% to 19.4(0.0)% CR [Mean(SEM)], and participants achieved 11.9(0.7)% CR and were in the zone. CONCLUSION The results highlight the challenges of: 1) setting a single CR goal vs. a range of acceptable values, and 2) obtaining real-time and valid measures of CR adherence to facilitate adherence.
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Effect of oral contraceptives on energy balance in women: A review of current knowledge and potential cellular mechanisms.
Metz, L, Isacco, L, Redman, LM
Metabolism: clinical and experimental. 2022;:154919
Abstract
Body weight management is currently of major concern as the obesity epidemic is still a worldwide challenge. As women face more difficulties to lose weight than men, there is an urgent need to better understand the underlying reasons and mechanisms. Recent data have suggested that the use of oral contraceptive (OC) could be involved. The necessity of utilization and development of contraceptive strategies for birth regulation is undeniable and contraceptive pills appear as a quite easy approach. Moreover, OC also represent a strategy for the management of premenstrual symptoms, acne or bulimia nervosa. The exact impact of OC on body weight remains not clearly established. Thus, after exploring the potential underlying mechanisms by which OC could influence the two side of energy balance, we then provide an overview of the available evidence regarding the effects of OC on energy balance (i.e. energy expenditure and energy intake). Finally, we highlight the necessity for future research to clarify the cellular effects of OC and how the individualization of OC prescriptions can improve long-term weight loss management.