Daily Endocrinology Research Analysis
Three studies reshape endocrinology and metabolism: (1) macrophage KLK7 drives inflammatory infiltration in visceral adipose tissue and emerges as a druggable target; (2) FGF21 modulates the HPA axis and adrenal regeneration after Cushing’s syndrome with clear sex-dependent effects; (3) in a 9-year Chinese cohort, stricter WHO BMI thresholds better stratify cardiometabolic risk than current China criteria.
Summary
Three studies reshape endocrinology and metabolism: (1) macrophage KLK7 drives inflammatory infiltration in visceral adipose tissue and emerges as a druggable target; (2) FGF21 modulates the HPA axis and adrenal regeneration after Cushing’s syndrome with clear sex-dependent effects; (3) in a 9-year Chinese cohort, stricter WHO BMI thresholds better stratify cardiometabolic risk than current China criteria.
Research Themes
- Adipose immunometabolism and protease targeting (KLK7)
- Sex-specific endocrine axis modulation (FGF21 and HPA/adrenal recovery)
- Population BMI cut-offs and cardiometabolic risk stratification
Selected Articles
1. The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.
Using macrophage-specific KLK7 knockout mice, the study shows that KLK7 drives inflammatory macrophage recruitment and activation in visceral adipose tissue under high-fat diet. Human validation in 1,143 visceral adipose samples linked KLK7 expression to migration/inflammatory pathways, and serum KLK7 correlated with circulating inflammatory markers in obese patients with diabetes.
Impact: KLK7 emerges as a mechanistic driver of adipose inflammation with convergent mouse-human evidence, nominating it as a therapeutic target to decouple adipose dysfunction from obesity.
Clinical Implications: Targeting KLK7 (e.g., inhibitors/biologics) may reduce visceral adipose inflammation and insulin resistance independent of weight loss; serum KLK7 could aid patient stratification for immunometabolic therapies.
Key Findings
- Macrophage-specific KLK7 knockout mice had lower systemic inflammation and reduced infiltration/activation of inflammatory macrophages in epididymal adipose tissue under high-fat diet.
- Klk7 deficiency reduced pro-inflammatory gene expression and limited macrophage migration via increased adhesion, hallmarks of obese adipose tissue macrophages.
- In 1,143 human visceral adipose tissue samples, KLK7 expression associated with cellular migration and inflammatory pathways; in a second cohort (n=60), serum KLK7 strongly correlated with circulating inflammatory markers.
Methodological Strengths
- Macrophage-specific genetic knockout model with high-fat diet challenge
- Large human validation (1,143 visceral adipose samples) plus independent serum cohort linking KLK7 to inflammation
Limitations
- Human data are cross-sectional, limiting causal inference
- No pharmacologic KLK7 inhibition tested in vivo to establish druggability and safety
Future Directions: Develop selective KLK7 inhibitors/biologics and test efficacy/safety in preclinical models and early-phase trials; evaluate serum KLK7 as a biomarker for patient selection and treatment response.
2. A comprehensive comparison of two commonly used BMI thresholds for non-communicable diseases and multimorbidity in the Chinese population.
In 13,519 Chinese adults followed for 9 years, overweight/obesity prevalence and risk stratification varied markedly by BMI criteria. WHO thresholds (≥23/≥25 kg/m2) identified more individuals at risk, and normal weight (vs borderline overweight) had substantially lower hazards for hypertension, dyslipidemia, and diabetes.
Impact: Establishes population-level consequences of BMI thresholds and supports adopting stricter cut-offs to improve cardiometabolic prevention in Chinese adults.
Clinical Implications: Clinicians and policymakers should consider WHO BMI thresholds for risk screening and prevention in Chinese adults; individuals with borderline overweight merit early lifestyle intervention.
Key Findings
- Overweight prevalence: 50.99% (WHO) vs 40.10% (China); obesity: 30.65% vs 10.97%, respectively.
- BMI showed positive or J-shaped associations with hypertension, dyslipidemia, diabetes, heart disease, stroke, and multimorbidity over 9 years.
- Compared to borderline overweight, normal weight was associated with lower risk of hypertension (HR 0.71), dyslipidemia (HR 0.71), and diabetes (HR 0.64).
Methodological Strengths
- Large national cohort (n=13,519) with 9-year follow-up
- Comparative evaluation of two widely used BMI thresholds with hazard modeling for multiple outcomes
Limitations
- Observational design with potential residual confounding
- Generalizability limited to middle-aged and older Chinese adults; adiposity measures beyond BMI were not assessed
Future Directions: Assess impacts of adopting WHO BMI thresholds on clinical workflows and outcomes; integrate central adiposity metrics to refine risk stratification.
3. Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after Cushing syndrome in mice.
In a mouse model of adrenal insufficiency after chronic corticosterone exposure, FGF21 increased ACTH and corticosterone secretion and modulated glucose–insulin homeostasis with sex-dependent effects. Tissue-specific Klb regulation across the HPA axis and sex-specific adrenal progenitor activation/remodeling suggest FGF21 as a candidate modulator of adrenal recovery after Cushing’s syndrome.
Impact: Defines a mechanistic link between FGF21 and HPA/adrenal recovery with clear sex differences, opening a path for sex-informed therapies after Cushing’s syndrome.
Clinical Implications: FGF21 pathway modulation may augment adrenal recovery after Cushing’s syndrome treatment; monitoring and dosing may need to be sex-specific if translated to humans.
Key Findings
- Recombinant human FGF21 increased ACTH and corticosterone secretion in mice with adrenal insufficiency after chronic corticosterone exposure.
- FGF21 overexpression altered glucose homeostasis and insulin regulation during CORT treatment and recovery with sex-specific effects.
- Tissue-specific Klb regulation across the HPA axis and sex-specific changes in adrenal progenitor activation, steroidogenic gene expression, and capsule remodeling during recovery.
Methodological Strengths
- Use of both recombinant FGF21 and transgenic overexpression in male and female mice
- Multi-level assessment: hormones, metabolism, tissue morphology, and gene expression across the HPA axis
Limitations
- Preclinical mouse model limits direct clinical translatability
- No human validation and limited functional outcomes beyond endocrine/molecular endpoints
Future Directions: Test FGF21 analogs in models of post-Cushing adrenal insufficiency with functional outcomes; investigate sex-specific dosing and safety; explore Klb tissue targeting.