The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series.

BACKGROUND: Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. AIM: This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. METHODS: In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. RESULTS: Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. CONCLUSION: Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1.

Association between Serum Vitamin D Metabolites and Metabolic Function in Healthy Asian Adults.

The association between low vitamin D status and the development of type 2 diabetes mellitus is well established; however, intervention trials that increased serum vitamin D (through ultraviolet B exposure or dietary supplementation) provide mixed outcomes. Recent evidence suggests that metabolites directly related to vitamin D receptor activation-1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3-may be better markers of vitamin D repletion status. We tested the hypothesis that a vitamin D metabolite (VDM) index, calculated as the sum of normalized fasting serum concentrations of 1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3, is associated with metabolic function. We measured subcutaneous and visceral adipose tissue volume, intrahepatic triglyceride content, maximum oxygen uptake, insulin sensitivity (4 h hyperinsulinemic-euglycemic clamp), and insulin secretion (3 h meal tolerance test with mathematical modeling) and calculated the VDM index in 65 healthy Asian adults. Subjects with a low VDM index had lower peripheral insulin sensitivity and beta-cell function compared to subjects with a high VDM index (both p < 0.05), matched for age, sex, BMI, and serum 25-hydroxyvitamin D3. Serum 25-hydroxyvitamin D3 was not associated with peripheral insulin sensitivity or beta-cell function. Our results suggest that, rather than enhancing vitamin D substrate availability, upregulation of vitamin D action is more likely to lead to improvements in glucose homeostasis.

Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians.

BACKGROUND: The importance of ectopic fat deposition and physical fitness in the pathogenesis of insulin resistance and beta cell dysfunction in subjects from the nonobese Asians is not known. MATERIALS AND METHODS: We conducted a cross-sectional study and measured insulin sensitivity (M value; 4-hour hyperinsulinaemic-euglycaemic clamp), insulin secretion rate (3-hour mixed meal tolerance test with oral minimal modelling), percent body fat, visceral adipose tissue, intramyocellular and intrahepatic lipid contents (magnetic resonance imaging and spectroscopy), cardiorespiratory fitness (VO2 max; graded exercise test) and habitual physical activity (short International Physical Activity Questionnaire) in 60 healthy nonobese Asian subjects (BMI = 21.9 ± 1.7 kg/m2 , age = 41.8 ± 13.4 years). RESULTS: M was inversely associated with percent body fat (r = -0.460, P < 0.001), visceral fat (r = -0.623, P < 0.001) and liver fat (r = -0.601, P < 0.001), whereas insulin secretion correlated positively with these adiposity indices (percent body fat: r = 0.303, P = 0.018; visceral fat: r = 0.409, P = 0.010; hepatic fat: r = 0.393, P = 0.002). VO2 max correlated negatively with insulin secretion rate (r = -0.420, P < 0.001) and positively with M (r = 0.658, P < 0.001). The amount of vigorous physical activity was positively associated with VO2 max (r = 0.682, P < 0.001). Multiple stepwise linear regression analyses indicated that VO2 max, age, and IHTG or VAT were independent determinants of insulin sensitivity and secretion (adjusted R2  = 69% and 33%, respectively, P < 0.001). CONCLUSIONS: Increased ectopic fat deposition is associated with reduced insulin sensitivity and increased insulin secretion in healthy nonobese Asians. Poor cardiorespiratory fitness, likely due to inadequate participation in vigorous exercise, is strongly related to suboptimal metabolic function. Interventions to encourage engagement in physical activity may thus be important for improving metabolic health in nonobese Asians.