Obesity最新文献

Objective

Topiramate is a medication used off-label, or in combination with phentermine, for the management of obesity. However, its mechanism of action remains elusive. As many obesity medications target the brain, we aimed to determine if topiramate influences the activity of hypothalamic melanocortin neurons known to regulate energy balance.

Methods

Transgenic mice expressing a fluorescent protein in either “orexigenic” neuropeptide Y/agouti-related peptide (NPY/AgRP) or “anorexigenic” pro-opiomelanocortin (POMC) neurons were used to perform whole-cell patch clamp electrophysiology experiments in the arcuate nucleus (ARC) of the hypothalamus.

Results

Topiramate (1 μM) strongly inhibited NPY/AgRP neuron electrical excitability. Despite topiramate's well-known actions at GABA_A receptors, we demonstrate that the topiramate-induced inhibition of NPY/AgRP neurons does not involve GABA_A receptors. The effects of topiramate on NPY/AgRP neurons were suppressed by inhibitors of synaptic transmission and after blockade of GABA_B receptors or potassium channels. In contrast, topiramate had negligible influence on the activity of POMC neurons.

Conclusions

This study is the first demonstration that topiramate strongly inhibits the activity of ARC NPY/AgRP neurons and suggests that enhanced GABAergic tone to these neurons mediates this effect. The ability of topiramate to inhibit the orexigenic NPY/AgRP neurons may underlie some of its weight-lowering properties.

Objective

The relation between genetically predicted BMI (gBMI) and actual BMI may have health effects. This study examines the relationship between deviations from gBMI and all-cause mortality in 208,146 UK Biobank participants.

Methods

We derived gBMI from polygenic risk scores, with deviations calculated as the difference between observed and predicted BMI. Cox proportional hazards models are adjusted for confounders and current BMI.

Results

Downward deviations (> 2 SD below gBMI) were associated with significantly increased mortality (HR: 1.25, 95% CI: 1.01–1.55), whereas upward deviations (> 2 SD above) showed no significant effect (HR: 1.10, 95% CI: 0.93–1.29). The mortality exhibited the known nonlinear J-shaped association with observed BMI, here lowest at BMI ~22 kg/m², but this nadir varied by genetic predisposition; thus, for individuals with high gBMI, lowest mortality occurred at higher observed BMI (24–26 kg/m²), while those with low or medium gBMI showed sharper increases in mortality at higher BMI.

Conclusions

These findings highlight the possible importance of aligning current BMI to genetic predisposition, and future research should examine BMI deviations and their long-term health effects. This perspective may inform personalized obesity management strategies to optimize health outcomes.

Objective

This study aimed to examine sex-stratified associations between meeting recommended sleep duration and adiposity in 10-year-old children.

Methods

Using the GUSTO cohort (51% boys, 10.2 ± 0.2 years), we evaluated the associations of meeting sleep duration recommendations (total daily sleep duration of ≥ 9 h, caregiver-reported and actigraphy) throughout the week with obesity and BMI z-scores (N = 638), glycoprotein acetyls (n = 436), fat mass measured by quantitative magnetic resonance (n = 528), and abdominal adipose tissue volumes measured by magnetic resonance imaging (N = 377). Multivariable linear and logistic regressions were used, adjusted for ethnicity and maternal education.

Results

Boys, but not girls, whose caregiver-reported sleep duration met recommendations throughout the entire week had a lower risk of obesity (BMIz > 2.0) (OR = 0.49, 95% CI 0.27–0.87), BMIz (0.34 ± 0.16 vs. 0.98 ± 0.12) (p = 0.001), glycoprotein acetyls levels (0.65 ± 0.01 mmol/L vs. 0.70 ± 0.01 mmol/L) (p < 0.001), total fat mass (8.77 ± 0.69 kg vs. 11.31 ± 0.51 kg) (p = 0.002), and deep subcutaneous (492 ± 86 mL vs. 729 ± 56 mL) (p = 0.014), superficial subcutaneous (651 ± 85 mL vs. 888 ± 55 mL) (p = 0.013), and visceral (415 ± 51 mL vs. 557 ± 33 mL) (p = 0.013) adipose tissue volumes.

Conclusions

Interventions to help children attain recommended sleep duration for weekdays and weekends may reduce abdominal and total adiposity, especially in boys.

Objective

This study aimed to characterize the reasons for treatment discontinuation with injectable semaglutide or tirzepatide for obesity in regular clinical practice.

Methods

This cross-sectional study used electronic health record data between January 2022 and December 2024 from a single integrated health system in Ohio and Florida. The primary reason for treatment discontinuation was examined in a randomly selected sample of adults with overweight or obesity and without type 2 diabetes who initiated injectable semaglutide or tirzepatide and discontinued treatment within the first year.

Results

We randomly selected 288 patients; 145 received semaglutide and 143 tirzepatide. Overall, 137 patients (47.6%) discontinued their medication due to cost or insurance-related issues, 42 (14.6%) due to inability to tolerate the side effects, 34 (11.8%) as they were unable to fill the medication due to shortages, 7 (2.4%) as they switched to a compounded medication, and 5 (1.7%) due to unsatisfactory weight loss; 31 (10.8%) discontinued for other reasons, and for 32 (11.1%) patients the discontinuation reason was not specified in the electronic health record.

Conclusions

High cost or insurance-related issues are the most common reasons for treatment discontinuation with semaglutide or tirzepatide for obesity. Our findings highlight the need for policies to address cost and could inform discussions between healthcare providers and patients concerning cost and side effects.

Objective

Fatty acids in adipose tissue are key structural and metabolic regulators of cardiometabolic health, but the genetic architecture governing depot-specific composition in subcutaneous (SAT) and visceral adipose tissue (VAT) is not well defined.

Methods

We used MRI-derived estimates of fatty acid composition in SAT and VAT from 33,583 UK Biobank participants to perform genome-wide association studies. Functional annotation, fine mapping, colocalization, and expression QTL analyses were conducted to prioritize likely causal variants and explore mechanisms.

Results

We identified six loci associated with adipose tissue fatty acid composition, including both shared (PKD2L1, INSIG1) and depot-specific associations (LEKR1 and KLF14 for SAT; CDCA2 for VAT). The strongest association, rs603424-G (near PKD2L1), was linked to higher monounsaturated and polyunsaturated fatty acids, lower saturated fatty acids, and increased SCD1 expression in SAT and VAT, suggesting a role in desaturation and lipid remodeling. Several loci were linked to cardiometabolic outcomes including type 2 diabetes, hypertension, and cholelithiasis, with functional evidence supporting gene–diet interactions at the PKD2L1 locus.

Conclusions

Our findings uncover genetic determinants of human adipose tissue fatty acid composition, highlight depot-specific regulation, and point to SCD1 as a potential metabolic regulator. These results deepen understanding of lipid metabolism and its links to cardiometabolic risk.

Objective

This study compared the effects of a very low-energy diet (VLED), alone or combined with sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB), on glucose-dependent insulinotropic polypeptide (GIP) and glucagon concentrations, hormones likely to play a role in weight loss maintenance.

Methods

Participants with severe obesity underwent 10 weeks of VLED alone (n = 15) or combined with SG (n = 15) or RYGB (n = 14). Plasma concentrations of glucagon and GIP (fasting and the first 60 min of a meal), insulin sensitivity, respiratory quotient, and resting energy expenditure (REE) were measured at pre- and post-intervention. Differences in hormone concentrations between groups at follow-up and associations between hormones and metabolic outcomes were evaluated.

Results

Fasting glucagon concentrations were higher, while postprandial GIP concentrations were lower, after RYGB compared to SG. An increase in postprandial glucagon was associated with a decrease in Matsuda index in the RYGB group and with an increase in REE in all groups. An increase in fasting GIP was correlated with an increase in HOMA-IR.

Conclusions

RYGB was associated with lower postprandial GIP and greater glucagon concentrations compared with other groups. These hormonal changes are likely to impact REE, as well as insulin sensitivity, potentially modulating the likelihood of weight loss maintenance.

Trial Registration: ClinicalTrials.gov identifier NCT04051190.

Objective

This study aimed to examine the association of BMI with cognitive performance in individuals with diabetes or prediabetes.

Methods

Among Diabetes Prevention Program Outcomes Study (DPPOS) participants, BMI was categorized as normal (< 25 kg/m²), overweight (25 to < 30 kg/m²), or obesity (≥ 30 kg/m²). Cognitive tests included the Brief Spanish English Verbal Learning Test (B-SEVLT) and the Digit Symbol Substitution test (DSST). The relationship between BMI at DPPOS Year 8 (Y8) visit and cognitive test scores at Y8, Y10, and Y15 visits was ascertained via linear mixed models accounting for repeated measures. Analogous models related BMI to Modified Mini-Mental State exam (3MS) score at Y15.

Results

A total of 2285 participants (mean ± SD age 51.1 ± 10.0 years; 67.7% female; 31% with overweight; and 60% with obesity at DPPOS Y8) completed cognitive assessments. Those with overweight or obesity at Y8 had a slower decline in B-SEVLT immediate and delayed recall, compared with those with normal BMI; 3MS performance was higher among individuals with overweight or obesity compared to those with normal BMI at Y15.

Conclusions

Among individuals with prediabetes or diabetes in DPPOS, overweight or obesity was associated with slower decline in verbal learning and memory compared with those with normal BMI.

Objective

This study aimed to investigate the associations of body roundness index (BRI) with cardiometabolic disease (CMD), cardiometabolic multimorbidity (CMM), and all-cause mortality, while evaluating its impact across different stages of CMM progression.

Methods

In this prospective cohort study, 87,902 participants from the Kailuan cohort were categorized into BRI quartiles. Cox models estimated hazard ratios (HRs) and 95% CIs for the first occurrence of cardiometabolic disease (FCMD), CMM, and mortality. Multistate models assessed BRI's role across CMM progression.

Results

Over a median follow-up of 13.68 years, 21,636 participants developed FCMD, 2114 developed CMM, and 14,782 died. Elevated BRI increased risks of FCMD, CMM, and mortality in Cox models. Multistate analysis revealed differential BRI effects across CMM progression: participants in the highest versus lowest BRI quartile showed HRs of 2.08 (1.99–2.17) for healthy-to-FCMD transition, 1.61 (1.38–1.88) for FCMD-to-CMM transition, and 1.09 (1.03–1.16), 0.99 (0.89–1.10), and 0.73 (0.54–0.99) for mortality from the healthy state, FCMD, and CMM, respectively. BRI's impact varied by disease type (diabetes mellitus, myocardial infarction, stroke) and sex, with stronger associations in females.

Conclusions

Our findings emphasize dynamic BRI monitoring as a biomarker for early CMM risk identification and prognostic assessment, necessitating disease- and sex-specific prevention strategies.