We investigated whether ultra-processed foods affect energy intake in 20 weight-stable adults, aged (mean ± SE) 31.2 ± 1.6 years and BMI = 27 ± 1.5 kg/m2. Subjects were admitted to the NIH Clinical ...Center and randomized to receive either ultra-processed or unprocessed diets for 2 weeks immediately followed by the alternate diet for 2 weeks. Meals were designed to be matched for presented calories, energy density, macronutrients, sugar, sodium, and fiber. Subjects were instructed to consume as much or as little as desired. Energy intake was greater during the ultra-processed diet (508 ± 106 kcal/day; p = 0.0001), with increased consumption of carbohydrate (280 ± 54 kcal/day; p < 0.0001) and fat (230 ± 53 kcal/day; p = 0.0004), but not protein (−2 ± 12 kcal/day; p = 0.85). Weight changes were highly correlated with energy intake (r = 0.8, p < 0.0001), with participants gaining 0.9 ± 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 ± 0.3 kg (p = 0.007) during the unprocessed diet. Limiting consumption of ultra-processed foods may be an effective strategy for obesity prevention and treatment.
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•20 inpatient adults received ultra-processed and unprocessed diets for 14 days each•Diets were matched for presented calories, sugar, fat, fiber, and macronutrients•Ad libitum intake was ∼500 kcal/day more on the ultra-processed versus unprocessed diet•Body weight changes were highly correlated with diet differences in energy intake
Hall et al. investigated 20 inpatient adults who were exposed to ultra-processed versus unprocessed diets for 14 days each, in random order. The ultra-processed diet caused increased ad libitum energy intake and weight gain despite being matched to the unprocessed diet for presented calories, sugar, fat, sodium, fiber, and macronutrients.
Objective
To measure long‐term changes in resting metabolic rate (RMR) and body composition in participants of “The Biggest Loser” competition.
Methods
Body composition was measured by dual energy ...X‐ray absorptiometry, and RMR was determined by indirect calorimetry at baseline, at the end of the 30‐week competition and 6 years later. Metabolic adaptation was defined as the residual RMR after adjusting for changes in body composition and age.
Results
Of the 16 “Biggest Loser” competitors originally investigated, 14 participated in this follow‐up study. Weight loss at the end of the competition was (mean ± SD) 58.3 ± 24.9 kg (P < 0.0001), and RMR decreased by 610 ± 483 kcal/day (P = 0.0004). After 6 years, 41.0 ± 31.3 kg of the lost weight was regained (P = 0.0002), while RMR was 704 ± 427 kcal/day below baseline (P < 0.0001) and metabolic adaptation was −499 ± 207 kcal/day (P < 0.0001). Weight regain was not significantly correlated with metabolic adaptation at the competition's end (r = −0.1, P = 0.75), but those subjects maintaining greater weight loss at 6 years also experienced greater concurrent metabolic slowing (r = 0.59, P = 0.025).
Conclusions
Metabolic adaptation persists over time and is likely a proportional, but incomplete, response to contemporaneous efforts to reduce body weight.
The carbohydrate-insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate ...diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m
were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal
) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal
) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d
less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d
less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate-insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108 .
BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Abstract
Background
African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of β-cell glucose sensitivity (β-GS) and ...insulin clearance in hyperinsulinemia in AA adults is unclear.
Objective
Using a cross-sectional study design, we compared β-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT).
Methods
Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index–matched AA and NHW cadaveric donors (n = 10).
Results
Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. β-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs.
Conclusions
In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels.
The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals' susceptibility to weight gain. ...Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual's capacity to oxidize dietary fat is a metabolic determinant of weight change.
Along with the rising incidence of obesity, there has been an increase in patients diagnosed with early-onset colorectal cancer (<50 years old). In colorectal cancer, worse patient survival is ...associated with certain cytokine expression and downregulation of peroxisome proliferator activated receptor gamma expression. The effects of the obesity hormone leptin and macrophage-specific metabolite itaconate on these mechanisms are poorly understood. We investigated their impact on peroxisome proliferator activated receptor gamma and macrophage cytokine expression in vitro.
M2-like macrophages were treated with either leptin, 4-octyl itaconate, or dimethyl itaconate in a dose- and time-dependent manner. Gene expression after treatment with 4 doses (D1-4) of each compound was analyzed at 4 time points (3, 6, 18, and 24 hours).
Peroxisome proliferator activated receptor gamma was downregulated after 4-octyl itaconate treatment at 18 hours (FC -32.67, P ≤ .001). Interleukin-8 was upregulated after leptin and dimethyl itaconate treatment at 6 hours (FC 26.35 at D4, P ≤ .001, and FC 23.26 at D3, P = .006). Dimethyl itaconate upregulated IL-1β at 24 hours (FC 18.00 at D4, P ≤ .001). Tumor necrosis factor-α showed maximum downregulation after 4-octyl itaconate at 18 hours (FC -103.25 at D4, P ≤ .001).
Itaconate downregulates peroxisome proliferator activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Itaconate provides a link between obesity and colorectal cancer and may be a key regulator in early-onset colorectal cancer.
Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. EPO treatment in mice on high-fat diets (HFD) improved glucose ...tolerance and decreased body weight gain via reduced fat mass in males and ovariectomized females. The decreased fat accumulation with EPO treatment during HFD in ovariectomized females was abrogated with estradiol supplementation, providing evidence for estrogen-related gender-specific EPO action in metabolic regulation. In this study, we examined the cross-talk between estrogen mediated through estrogen receptor α (ERα) and EPO for the regulation of glucose metabolism and fat mass accumulation.
Wild-type (WT) mice and mouse models with ERα knockout (ERα−/−) and targeted deletion of ERα in adipose tissue (ERαadipoKO) were used to examine EPO treatment during high-fat diet feeding and after diet-induced obesity.
ERα−/− mice on HFD exhibited increased fat mass and glucose intolerance. EPO treatment on HFD reduced fat accumulation in male WT and ERα−/− mice and female ERα−/− mice but not female WT mice. EPO reduced HFD increase in adipocyte size in WT mice but not in mice with deletion of ERα independent of EPO-stimulated reduction in fat mass. EPO treatment also improved glucose and insulin tolerance significantly greater in female ERα−/− mice and female ERαadipoKO compared with WT controls. Increased metabolic activity by EPO was associated with browning of white adipocytes as shown by reductions in white fat-associated genes and induction of brown fat-specific uncoupling protein 1 (UCP1).
This study clearly identified the role of estrogen signaling in modifying EPO regulation of glucose metabolism and the sex-differential EPO effect on fat mass regulation. Cross-talk between EPO and estrogen was implicated for metabolic homeostasis and regulation of body mass in female mice.
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•Erythropoietin regulates fat mass in male but not female mice on high-fat diets.•Female estrogen receptor alpha deletion restores erythropoietin fat mass regulation.•Estrogen receptor alpha deletion increases erythropoietin regulation of glucose tolerance.•Erythropoietin reduced white fat-associated genes and increased uncoupling protein 1.•Erythropoietin and estrogen cross-talk is implicated for metabolic homeostasis.
Dopamine, a key neurotransmitter in the autonomic nervous system participating in the homeostatic balance between sympathetic and parasympathetic divisions, is involved in food intake regulation.
We ...investigated whether dopamine is altered by acute fasting or overfeeding diets with varying macronutrient content.
Ninety-nine healthy subjects underwent 24-h dietary interventions including eucaloric feeding, fasting, and five different overfeeding diets in a crossover design. Overfeeding diets (200% of eucaloric requirements) included one diet with 3%-protein (low-protein high-fat overfeeding-LPF: 46%-fat), three diets with 20%-protein, and a diet with 30%-protein (44%-fat). Urine was collected for 24 h and urinary dopamine concentration was quantified by high-performance liquid chromatography. Plasma pancreatic polypeptide (PP) concentration, an indirect marker of parasympathetic activity, was measured prior to and after each diet after an overnight fast.
During 24-h of fasting, dopamine decreased on average by ~14% compared to eucaloric conditions, whereas PP increased by two-fold (both
< 0.001). Lower dopamine during 24-h fasting correlated with increased PP (r = -0.40,
< 0.001). Similarly, on average urinary dopamine decreased during LPF by 14% (
< 0.001) and lower dopamine correlated with increased PP (r = -0.31,
= 0.01). No changes in dopamine and PP concentrations were observed during other overfeeding diets (all
> 0.05).
Dopamine concentrations decrease during short-term fasting and overfeeding with a low-protein diet. As both dietary conditions have in common protein deficit, the correlation between dopamine and PP suggests a compensatory mechanism underlying the shift from sympathetic to parasympathetic drive during dietary protein deprivation.
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