Daily Endocrinology Research Analysis
Analyzed 124 papers and selected 3 impactful papers.
Summary
Analyzed 124 papers and selected 3 impactful articles.
Selected Articles
1. Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity.
This mechanistic study identifies a palmitic acid–CREBZF–c-JUN axis that impairs VAT ICOShi Treg stability and suppressive function, driving adipose inflammation and systemic metabolic disturbances. CREBZF loss enhances Treg suppressive capacity and mitigates obesity-associated inflammation, with human VAT Tregs showing elevated CREBZF inversely correlated with FOXP3 activity.
Impact: It uncovers a previously unrecognized immunometabolic mechanism linking dietary saturated fat to Treg dysfunction and metabolic disease, highlighting CREBZF as a tractable target.
Clinical Implications: Although preclinical, the work nominates CREBZF (and its interaction with c-JUN/Foxp3) as a therapeutic axis to restore VAT Treg function, suggesting avenues for diet-informed and pharmacologic immunometabolic interventions in obesity and type 2 diabetes.
Key Findings
- Palmitic acid (but not oleic acid) induces Crebzf in VAT Tregs, impairing ICOShi Treg suppressive function and driving VAT inflammation.
- Crebzf deficiency reduces diet-induced obesity and inflammation; adoptive transfer of Crebzf-deficient ICOShi Tregs more effectively alleviates HFHS-induced metabolic disorders than wild-type Tregs.
- CREBZF interacts with c-JUN to inhibit Foxp3 activity, destabilizing ICOShi Tregs and reducing inhibitory cytokine production.
- Human VAT Tregs show elevated CREBZF with a negative correlation to FOXP3 activity, supporting translational relevance.
Methodological Strengths
- Multi-system validation including diet-induced and genetic obesity models, adoptive transfer, and human VAT Treg analyses.
- Mechanistic dissection of protein interactions (CREBZF–c-JUN–FOXP3) linking transcriptional control to Treg function.
Limitations
- Predominantly murine models; causal therapeutic translation in humans remains to be established.
- Human data are correlative (elevated CREBZF and inverse FOXP3 activity) without interventional proof in patients.
Future Directions: Test pharmacologic inhibition of CREBZF or disruption of CREBZF–c-JUN in vivo, evaluate diet-saturated fat modification on VAT Treg phenotypes in humans, and develop biomarkers of VAT Treg dysfunction for patient stratification.
Regulatory T (Treg) cells in visceral adipose tissue (VAT) play essential roles in systemic metabolic homeostasis under distinct physiological and pathological conditions. However, the metabolic cues that drive Treg cell subset specialization in the obese VAT niche remain elusive. Here, we demonstrated that palmitic acid instigated chronic VAT inflammation and systemic metabolic disturbance by compromising the immunosuppressive function of the ICOShi Treg subset. Palmitic acid, but not oleic acid, activated Crebzf expression in VAT Treg cells from HFHS diet-induced obese and ob/ob mice. Crebzf deficiency significantly attenuated diet-induced obesity and inflammation by upregulating the suppressive function of VAT ICOShi Treg cells. Moreover, adoptive transfer of Crebzf-deficient ICOShi Treg cells into Rag1-/- mice alleviated HFHS diet-induced inflammation and metabolic disorders more effectively than transfer of Crebzf-sufficient ICOShi Treg cells. Mechanistically, CREBZF interacted with c-JUN to inhibit Foxp3 activity, thereby impairing the stability and inhibitory cytokine production of ICOShi Treg cells. In human subjects, CREBZF levels in VAT Treg cells were elevated and negatively correlated with FOXP3 activity. Collectively, these findings uncover a specific ICOShi Treg subset that responds to palmitic acid, thereby coupling obesogenic signals to VAT remodeling and systemic metabolic homeostasis.
2. Influence of Cardiometabolic Status on Cardiovascular Effects of Oral Menopausal Hormone Therapy.
In secondary analyses of two large RCTs, baseline lipids strongly modified CHD risk with oral MHT. Untreated LDL ≥190 mg/dL or higher LDL/HDL ratios increased CHD risk (notably with CEE+MPA), whereas favorable lipid profiles or prior hyperlipidemia treatment did not confer excess risk.
Impact: These data operationalize lipid-based risk stratification for oral MHT, informing safer patient selection across age groups.
Clinical Implications: Check fasting lipid profiles before initiating oral CEE or CEE+MPA. Avoid or reconsider oral CEE+MPA in women with very high untreated LDL (≥190 mg/dL) or high LDL/HDL ratios; consider alternative routes/regimens. Treated hyperlipidemia may mitigate risk.
Key Findings
- In CEE+MPA, untreated LDL ≥190 mg/dL more than doubled CHD risk (HR 2.77; 95% CI 1.42–5.40; P-trend=.002), while LDL <130 mg/dL showed no excess risk (HR 0.59; 95% CI 0.31–1.10).
- Higher LDL/HDL ratios increased CHD risk (e.g., ratio ≥4: HR 1.76; 95% CI 1.08–2.88; P-trend=.008); similar but nonsignificant trends in CEE-alone.
- HDL ≥60 mg/dL appeared protective compared with HDL <50 mg/dL (P-trend=.02). Blood pressure, glucose, triglycerides, and metabolic syndrome did not modify MHT-related CHD risk.
- Prior hyperlipidemia treatment was not associated with increased CHD risk on MHT.
Methodological Strengths
- Secondary analysis of two large, double-blind, placebo-controlled RCTs with adjudicated CHD outcomes.
- Robust effect-modification analyses across lipid strata and consistency across age subgroups.
Limitations
- Secondary analysis; potential residual confounding and multiple comparisons.
- Generalizability limited to trial populations and to oral CEE/CEE+MPA regimens.
Future Directions: Prospective, stratified trials to test lipid-guided MHT selection, assessment of non-oral routes (e.g., transdermal) in high-LDL phenotypes, and integration of lipid metrics into decision aids.
OBJECTIVE: To assess risk of adverse cardiovascular outcomes from menopausal hormone therapy (MHT) by cardiometabolic status. METHODS: Secondary analysis of two double-blind placebo-controlled randomized controlled trials of conjugated equine estrogens ([CEE] 0.625 mg/d) or CEE with medroxyprogesterone acetate ([MPA] 2.5 mg/d) compared with placebo in postmenopausal women aged 50-79 years. The primary outcome was coronary heart disease ([CHD], nonfatal myocardial infarction or CHD death). Cardiometabolic status was evaluated by lipid profile, blood pressure, blood glucose, and presence of metabolic syndrome (MetS). RESULTS: The CEE-alone trial enrolled 10,739 participants who had undergone hysterectomy, and the CEE+MPA trial enrolled 16,608 participants with an intact uterus. Randomization to oral MHT did not increase CHD risk in participants with a history of treated hyperlipidemia or in untreated participants with favorable lipid profiles, but risk increased in those with unfavorable lipid profiles. In the CEE+MPA trial, the CHD risk in untreated participants with normal low-density lipoprotein (LDL) cholesterol levels (less than 130 mg/dL) was similar to that of placebo-treated participants (hazard ratio [HR] 0.59; 95% CI, 0.31-1.10); however, for elevated LDL 190 mg/dL or higher, the risks were more than doubled (HR 2.77; 95% CI, 1.42-5.40; P-trend=.002). Risk of CHD increased with higher LDL/high-density lipoprotein (HDL) ratios (ratio less than 2.5: HR 0.73; 95% CI, 0.39-1.37 vs ratio 4 or higher: HR 1.76; 95% CI, 1.08-2.88 (P-trend=.008). Similar but nonsignificant risk patterns risk by increasing level of LDL/HDL ratio were seen for CEE-alone compared with placebo. Participants with HDL cholesterol levels 60 mg/dL or greater (vs less than 50 mg/dL) appeared to be at somewhat lower risk (HRs 0.68 and 1.24, P-trend=.02). The patterns for effect modification on CHD risk by untreated LDL cholesterol levels within 10-year age groups (50-59, 60-69, and 70-79 years) were consistent with the overall results in both trials. Blood pressure, blood glucose, triglycerides, or MetS did not modify CHD risk due to CEE or CEE+MPA. CONCLUSION: Higher baseline levels of LDL cholesterol when using CEE+MPA or lower levels of HDL cholesterol when using CEE resulted in an increased risk for CHD across all age groups. Prior treatment of hyperlipidemia demonstrated no increased risk of CHD in patients treated with CEE+MPA or CEE compared with those receiving placebo. Assessment of blood lipids could assist with selection of patients for treatment with CEE of CEE+MPA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT0000611.
3. The Impact of Non-AKI eGFR Variability on CKD Progression in Individuals With Type 2 Diabetes and Preserved Kidney Function.
In 98,322 adults with T2D and baseline eGFR >60, greater non-AKI eGFR variability over the first 5 years after diagnosis independently predicted progression to CKD G3b. Variability was quantified as the SD of residuals around each individual’s eGFR slope.
Impact: It identifies a practical, early longitudinal biomarker (non-AKI eGFR variability) for renal risk stratification in T2D before overt CKD.
Clinical Implications: Incorporate longitudinal eGFR variability into risk assessment for T2D with preserved function to flag high-risk patients for intensified renoprotective therapy (e.g., SGLT2 inhibitors, RAAS blockade) and closer monitoring.
Key Findings
- Non-AKI eGFR variability (SD of residuals around individual 5-year eGFR slope) was associated with subsequent progression to CKD G3b.
- The exposure window leveraged routine serum creatinine measurements over the first 5 years after T2D diagnosis.
- Association persisted in Cox models, supporting variability as an independent longitudinal predictor in preserved function.
Methodological Strengths
- Large nationwide, population-based cohort with standardized longitudinal creatinine data.
- Clear definition of variability distinct from acute kidney injury and robust time-to-event modeling.
Limitations
- Observational design may be subject to residual confounding and measurement variability in outpatient creatinine.
- Details of follow-up duration and competing risks are not provided in the abstract.
Future Directions: External validation across health systems; integrate eGFR variability into multivariable renal risk calculators; interventional studies to test whether reducing variability lowers CKD progression.
INTRODUCTION: Variability in estimated glomerular filtration rate (eGFR) has been associated with increased risks of mortality and chronic kidney disease (CKD) progression in people with type 2 diabetes mellitus (T2DM) and impaired kidney function. However, its significance in individuals with preserved kidney function remains unclear. METHODS: In this nationwide retrospective population-based study of individuals with T2DM, eGFR variability was calculated by fitting a linear regression model to longitudinal data to estimate both the individual eGFR slope over the 5-year period as well as the variability in model residuals provided by the SD of the model residuals using longitudinal serum creatinine (SCr) measurements obtained during the first 5 years after diagnosis. Cox proportional hazards models were then applied to assess the association between eGFR variability and progression to stage G3b CKD among participants with preserved kidney function. RESULTS: This study included 98,322 participants who had an eGFR > 60 ml/min per 1.73 m CONCLUSION: eGFR variability in the absence of acute kidney injury (AKI) is associated with CKD progression in individuals with T2DM and preserved kidney function.