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.
Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate ho
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.
BACKGROUND & AIMS: Various body mass index (BMI) thresholds are used to classify overweight and obesity in the Chinese population. We compared two commonly applied BMI classifications for Chinese population: World Health Organization (WHO) criteria (overweight: BMI≥23 kg/m METHODS: This research utilized data from the China Health and Retirement Longitudinal Study at baseline and after 9 years of follow-up (2011-2020). The sample comprised of 13,519 individuals in 2011 (mean age: 59 (10) years, mean BMI: 23.4 (3.6) kg/m RESULTS: Overweight prevalence was 50.99 % based on WHO criteria and 40.10 % based on China criteria. Obesity prevalence was 30.65 % and 10.97 %, respectively. BMI exhibited a positive or J-shaped association with multiple cardiometabolic factors (ie, hypertension, dyslipidemia, diabetes, heart disease, stroke) and multimorbidity. Individuals with normal weight experienced a lower risk of hypertension, dyslipidemia, diabetes [hazard ratio (95 % confidence interval): 0.71 (0.60-0.83), 0.71 (0.59-0.84), 0.64 (0.50-0.81), respectively] compared to those with borderline overweight. CONCLUSIONS: Different BMI classifications greatly affect overweight and obesity estimates and have implications for predicting morbidity and mortality. Although using the China Working Group's lenient BMI threshold (BMI<24 for normal and <28 for overweight) may help prevent multimorbidity and most NCDs, using the WHO's stricter BMI thresholds (BMI<23 and BMI<25 respectively) may offer even greater cardiometabolic benefits.
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.
BACKGROUND: Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response. METHODS: We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed. RESULTS: Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery. CONCLUSIONS: This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.