Search

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight-loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight-loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long-lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

Whole-room indirect calorimeters have been used to study human metabolism for more than a century. These studies have contributed substantial knowledge to the assessment of nutritional needs and the regulation of energy expenditure and substrate oxidation in humans. However, comparing results from studies conducted at different sites is challenging because of a lack of consistency in reporting technical performance, study design, and results. In May 2019, an expert panel was convened to consider minimal requirements for conducting and reporting the results of human whole-room indirect calorimeter studies. We propose Room Indirect Calorimetry Operating and Reporting Standards, version 1.0 (RICORS 1.0) to provide guidance to ensure consistency and facilitate meaningful comparisons of human energy metabolism studies across publications, laboratories, and clinical sites.

OBJECTIVE This study aimed to investigate a novel approach for determining the effects of energy-standardized dinner meals (high-fat and low-fat) on respiratory exchange ratio (RER) dynamics and metabolic flexibility. METHODS Using a randomized crossover study design, energy expenditure, RER, and macronutrient oxidation rates were assessed in response to a single dinner meal during an overnight stay in a whole-body room calorimeter. Eight healthy adults completed two overnight chamber stays while fed either a high-fat (60% fat, 20% carbohydrate [CHO], 20% protein; food quotient [FQ] = 0.784) or low-fat (20% fat, 60% CHO, 20% protein; FQ = 0.899) dinner containing 40% of daily energy requirements. RESULTS Following the low-fat meal, CHO oxidation first increased before decreasing, resulting in a 12-hour RER:FQ ratio close to 1.0 (0.986 ± 0.019, P = 0.06) and therefore resulting in a 12-hour equilibrated fat balance (29 ± 76 kcal/12 hours). Following the high-fat meal, participants had a RER:FQ ratio above 1.0 (1.061 ± 0.017, P

Over the past 10 to 15 years, intermittent fasting has emerged as an unconventional approach to reduce body weight and improve metabolic health beyond simple calorie restriction. In this review, we summarize findings related to Ramadan and Sunnah fasting. We then discuss the role of caloric restriction not only as an intervention for weight control, but importantly, as a strategy for healthy aging and longevity. Finally, we review the four most common intermittent fasting (IF) strategies used to date for weight management and to improve cardiometabolic health. Weight loss is common after IF, but does not appear to be different than daily caloric restriction when compared directly. IF may also provide additional cardiometabolic benefit, such as insulin sensitization, that is independent from weight loss. While no specific fasting regimen stands out as superior at this time, there is indeed heterogeneity in responses to these different IF diets. This suggests that one dietary regimen may not be ideally suited for every individual. Future studies should consider strategies for tailoring dietary prescriptions, including IF, based on advanced phenotyping and genotyping prior to diet initiation.

Objective Eating earlier in the daytime to align with circadian rhythms in metabolism enhances weight loss. However, it is unknown whether these benefits are mediated through increased energy expenditure or decreased food intake. Therefore, this study performed the first randomized trial to determine how meal timing affects 24-hour energy metabolism when food intake and meal frequency are matched. Methods Eleven adults with overweight practiced both early time-restricted feeding (eTRF) (eating from 8 am to 2 pm) and a control schedule (eating from 8 am to 8 pm) for 4 days each. On the fourth day, 24-hour energy expenditure and substrate oxidation were measured by whole-room indirect calorimetry, in conjunction with appetite and metabolic hormones. Results eTRF did not affect 24-hour energy expenditure (Δ = 10 ± 16 kcal/d; P = 0.55). Despite the longer daily fast (intermittent fasting), eTRF decreased mean ghrelin levels by 32 ± 10 pg/mL (P = 0.006), made hunger more even-keeled (P = 0.006), and tended to increase fullness (P = 0.06-0.10) and decrease the desire to eat (P = 0.08). eTRF also increased metabolic flexibility (P = 0.0006) and decreased the 24-hour nonprotein respiratory quotient (Δ = -0.021 ± 0.010; P = 0.05). Conclusions Meal-timing interventions facilitate weight loss primarily by decreasing appetite rather than by increasing energy expenditure. eTRF may also increase fat loss by increasing fat oxidation.

Objective Obesity prevalence in the United States (US) appears to be leveling, but the reasons behind the plateau remain unknown. Mechanistic insights can be provided from a mathematical model. The objective of this study is to model known multiple population parameters associated with changes in body mass index (BMI) classes and to establish conditions under which obesity prevalence will plateau. Design and Methods A differential equation system was developed that predicts population-wide obesity prevalence trends. The model considers both social and non-social influences on weight gain, incorporates other known parameters affecting obesity trends, and allows for country specific population growth. Results The dynamic model predicts that: obesity prevalence is a function of birth rate and the probability of being born in an obesogenic environment; obesity prevalence will plateau independent of current prevention strategies; and the US prevalence of obesity, overweight, and extreme obesity will plateau by about 2030 at 28%, 32%, and 9%, respectively. Conclusions The US prevalence of obesity is stabilizing and will plateau, independent of current preventative strategies. This trend has important implications in accurately evaluating the impact of various anti-obesity strategies aimed at reducing obesity prevalence.

Brown adipose tissue (BAT) generates heat in response to cold, and low BAT activity has been linked to obesity. However, recent studies were inconclusive as to whether BAT is involved in diet-induced thermogenesis and mitigates weight gain from prolonged overeating. Therefore, this study investigated whether BAT activity is related to metabolic adaptation arising from 8 weeks of overfeeding in humans.Fourteen men (aged 24 ± 3 years, BMI 24.5 ± 1.6 kg/mAt the end of 8 weeks of overfeeding, metabolic adaptation-defined as the percent increase in sleeping energy expenditure beyond that expected from weight gain-rose from -0.9 ± 3.9% to 4.7 ± 5.6% (P = 0.001). However, BAT thermal activity was unchanged (P = 0.81). Moreover, BAT thermal activity did not correlate with the degree of metabolic adaptation (P = 0.32) or with the change in body weight (P = 0.51).BAT thermal activity does not change in response to overfeeding, nor does it correlate with adaptive thermogenesis. Our data suggest that BAT does not mediate metabolic adaptation to overeating in humans.

On December 8-9, 2014, the Pennington Biomedical Research Center convened a scientific symposium to review the state-of-the-science and future directions for the study of developmental programming of obesity and chronic disease. The objectives of the symposium were to discuss: (i) past and current scientific advances in animal models, population-based cohort studies, and human clinical trials, (ii) the state-of-the-science of epigenetic-based research, and (iii) considerations for future studies.This symposium provided a comprehensive assessment of the state of the scientific field and identified research gaps and opportunities for future research in order to understand the mechanisms contributing to the developmental programming of health and disease.Identifying the mechanisms which cause or contribute to developmental programming of future generations will be invaluable to the scientific and medical community. The ability to intervene during critical periods of prenatal and early postnatal life to promote lifelong health is the ultimate goal. Considerations for future research including the use of animal models, the study design in human cohorts with considerations about the timing of the intrauterine exposure, and the resulting tissue-specific epigenetic signature were extensively discussed and are presented in this meeting summary.

The purpose of the study was to determine the effects of passaging on retention of donor phenotypic characteristics in primary human myotubes.Primary muscle cultures and serial passaged myotubes from physically active, sedentary lean, and individuals with type 2 diabetes were established. Maximal ATP synthesis capacity (ATPmax) and resting ATP flux (ATPase) in vivo were measured by (31) P magnetic resonance spectroscopy, type-I fibers and intramyocelluar lipid (IMCL) in vastus lateralis tissue were determined using immunohistochemistry techniques, and oxidative phosphorylation complexes (OXPHOS) were measured by Western immunoblotting. Similar in vitro measures for lipid and type-I fibers were made in myotubes, along with mitochondrial content measured by MitoTracker.Passage 4 and 5 measures for myotubes correlated positively with in vivo measurements for percent type-I fibers (P4: R(2) = 0.39, p = 0.02; P5: R(2) = 0.48, p = 0.01), ATPmax (P4: R(2) = 0.30, p = 0.03; P5: R(2) = 0.22, p = 0.05), and OXPHOS (P4: R(2) = 0.44, p = 0.04; P5: R(2) = 0.59, p = 0.006). No correlations were observed for IMCL. However, passage 4 measures for myotubes correlated with passage 5 measures for percent type-I fibers (R(2) = 0.49, p = 0.01), IMCL (R(2) = 0.80, p 0.001), and mitochondrial content (R(2) = 0.26, p = 0.03).Myotubes through the first two passages following immunopurification (referred to as passage 4 and 5) reflect the mitochondrial and type-I fiber content in vivo phenotype of the donor.

The overexpression of the adipose gene (adp/WDTC1) in mice inhibits lipid accumulation and improves the metabolic profile. Objective We evaluated subcutaneous fat adp expression in humans and its relation to metabolic parameters. Design, Setting and Methods Abdominal subcutaneous fat adp expression, insulin sensitivity (clamp) and respiratory quotient (RQ; indirect calorimetry) were assessed in: 36 obese and 56 BMI-, race- and sex-matched type 2 diabetic volunteers (Look AHEAD Adipose Ancillary Study); 37 non-diabetic Pima Indians including obese (n=18) and non-obese (n=19) subjects and; 62 non-obese non-diabetic subjects at the Pennington Center in the ADAPT study. Results In the Look AHEAD Study, adp expression normalized for cyclophilin B was higher in males vs. females (1.27±0.06 vs. 1.11±0.04; p

In addition to adipose tissue, recent studies suggest that skeletal muscle may also be a source of low-grade inflammation, particularly in inactive and/or overweight individuals. The aim of this study was to examine the presence of macrophages in skeletal muscle from obese subjects with type 2 diabetes (T2D) before and after a 9-month exercise program (vs. a non-exercising control group) (Study 1) and in young vs. elderly subjects (Study 2). In both studies, CD68(+) macrophages in vastus lateralis biopsies were determined by immunohistochemistry and inflammation gene expression measured. Macrophage content (%) was calculated by the number of macrophages per 100 muscle fibers. In Study 1, we found relatively low numbers (2-3%) of CD68(+) macrophages in skeletal muscle in obese T2D subjects (BMI = 37.3 ± 5.2 kg/m(2)), which were unchanged after a 9-month exercise program (P = 0.42). Similarly, in Study 2 (BMI = 27.1 ± 2.5 kg/m(2)), CD68(+) macrophages were relatively low in muscle (4-5%) and were not different between young and elderly individuals (P = 0.42). However, elderly subjects had twofold higher CD68 and CD206 gene expression (both P < 0.002) than young participants. In both studies, CD68(+) muscle macrophages were not associated with BMI. In conclusion, we found little evidence of macrophage accumulation in skeletal muscle in obese T2D subjects or in elderly individuals. A 9-month exercise program was not associated with a decrease in macrophage content.

BMI and waist circumference (WC) are used to identify individuals with elevated obesity-related health risks. The current thresholds were derived largely in populations of European origin. This study determined optimal BMI and WC thresholds for the identification of cardiometabolic risk among white and African-American (AA) adults. The sample included 2,096 white women, 1,789 AA women, 1,948 white men, and 643 AA men aged 18–64 years. Elevated cardiometabolic risk was defined as ≥2 risk factors (blood pressure ≥130/85 mm Hg; glucose ≥100 mg/dl; triglycerides ≥150 mg/dl; high-density lipoprotein-cholesterol

The purpose of this study was to examine sex and race differences in the relationship between anthropometric measurements and adiposity in white and African-American (AA) adults. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured with computed tomography (CT). Fat mass (FM) was measured with dual-energy-X-ray absorptiometry (DXA). Correlation coefficients were used to assess the relationship of waist circumference (WC) and BMI to VAT, SAT, and FM within sex-by-race groups. General linear models were used to compare relationships between WC or BMI, and adiposity across sex and race, within age groups (18–39 and 40–64 years). The sample included 1,667 adults (men: 489 white; 120 AA; women: 666 white, 392 AA). WC and BMI correlations were highest for FM and SAT compared to VAT. Women had higher FM levels than men regardless of WC, but the sex difference in FM was attenuated in younger AA adults with a high BMI. For a given level of WC or BMI, women had higher levels of SAT than men; however, significant interactions indicated that the relationship was not consistent across all levels of BMI and WC. Sex and race differences in VAT varied significantly with WC and BMI. In general, white adults had higher levels of VAT than AA adults at higher levels of BMI and WC. Sex differences, and in some instances race differences, in the relationships between anthropometry and fat-specific depots demonstrate that these characteristics need to be considered when predicting adiposity from WC or BMI.

The size of adipocytes influences their function suggesting a differential responsiveness to intervention. We hypothesized that weight loss in patients with type 2 diabetes mellitus (T2DM) predominantly decreases the size of large and very-large adipocyte subfractions in parallel with beneficial changes in serum adipokines and improved insulin sensitivity. A total of 44 volunteers from the Look Action for Health in Diabetes trial, who lost weight after 1-year of intense lifestyle intervention, were included. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), size of subcutaneous abdominal adipocytes (osmium fixation), and selected serum adipokines were measured. A 13% weight loss was accompanied by 46% improvement in insulin sensitivity (increased glucose disposal rate from 5.9+/-2.2 to 8.6+/-2.7 mg/min/kg fat-free mass, P

Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures.Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m(2)) were randomized to "control (CO)" = 100% energy requirements; "CR" = 25%; "caloric restriction and increased structured exercise (CR+EX)"= 12.5% CR + 12.5% increase in energy expenditure through exercise; or "low-calorie diet (LCD)" = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood.At baseline, increased liver lipid content (by MRS) correlated (P0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation.CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.

Objective: A non-silent polymorphism in the mitochondrial coding region of the ND1 gene, a subunit of reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase is associated with resting metabolic rate (RMR) in 245 non-diabetic Pima Indians. The purpose of this investigation was to determine the effect of the ND1 gene polymorphism on mitochondrial function in 14 male Pima Indians. Methods and Procedures: Seven subjects with an A at site 3547 of the ND1 gene (Ile at amino acid 81), and seven with a G at this site (Val) were studied. Mitochondria were isolated from 0.8 to 1.5 g of skeletal muscle obtained by needle biopsy of the lateral quadriceps muscle. In intact mitochondria, maximal (state-3) and resting (state-4) respiration rates were measured polarographically at 37 °C with a variety of single substrates or substrate combinations. Disrupted mitochondria were analyzed for maximal capacities through the entire electron transport chain (ETC) (NADH oxidase (NADHOX)), as well as through a segment of Complex I that is independent of the ND1 component (NADH-ferricyanide (NADH-FeCN) reductase). Results: Mitochondria were well coupled and exhibited higher respiratory control ratios (RCRs) than rodent muscle. There were no differences between the two groups for any of the measured parameters. Discussion: These results indicate that the cause of the observed association between RMR and the ND1 polymorphism is not related to in vitro mitochondrial function.

Objective: It is unclear if resting metabolic rate (RMR) and spontaneous physical activity (SPA) decrease in weight-reduced non-obese participants. Additionally, it is unknown if changes in SPA, measured in a respiratory chamber, reflect changes in free-living physical activity level (PAL). Research Methods and Procedures: Participants (N = 48) were randomized into 4 groups for 6 months: calorie restriction (CR, 25% restriction), CR plus structured exercise (CR+EX, 12.5% restriction plus 12.5% increased energy expenditure via exercise), low-calorie diet (LCD, 890 kcal/d supplement diet until 15% weight loss, then weight maintenance), and control (weight maintenance). Measurements were collected at baseline, Month 3, and Month 6. Body composition and RMR were measured by DXA and indirect calorimetry, respectively. Two measures of SPA were collected in a respiratory chamber (percent of time active and kcal/d). Free-living PAL (PAL = total daily energy expenditure by doubly labeled water/RMR) was also measured. Regression equations at baseline were used to adjust RMR for fat-free mass and SPA (kcal/d) for body weight. Results: Adjusted RMR decreased at Month 3 in the CR group and at Month 6 in the CR+EX and LCD groups. Neither measure of SPA decreased significantly in any group. PAL decreased at Month 3 in the CR and LCD groups, but not in the CR+EX group, who engaged in structured exercise. Changes in SPA in the chamber and free-living PAL were not related. Discussion: Body weight is defended in non-obese participants during modest caloric restriction, evidenced by metabolic adaptation of RMR and reduced energy expenditure through physical activity.