Daily Endocrinology Research Analysis

BACKGROUND: WNT signaling plays a key role in postnatal bone formation. Individuals with gain-of-function mutations in the WNT co-receptor LRP5 exhibit increased lower-body fat mass and potentially enhanced glucose metabolism, alongside high bone mass. However, the mechanisms by which LRP5 regulates fat distribution and its effects on systemic metabolism remain unclear. This study aims to explore the role of LRP5 in adipose tissue biology and its impact on metabolism. METHODS: Metabolic assessments and imaging were conducted on individuals with gain- and loss-of-function LRP5 mutations, along with age- and BMI-matched controls. Mendelian randomization analyses were used to investigate the relationship between bone, fat distribution, and systemic metabolism. Functional studies and RNA sequencing were performed on abdominal and gluteal adipose cells with LRP5 knockdown. RESULTS: Here we show that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity through cell-autonomous mechanisms, independent of its bone-related functions. LRP5 supports adipose progenitor cell function by activating WNT/β-catenin signaling and preserving valosin-containing protein (VCP)-mediated proteostasis. LRP5 expression in adipose progenitors declines with age, but gain-of-function LRP5 variants protect against age-related fat loss in the lower body. CONCLUSIONS: Our findings underscore the critical role of LRP5 in regulating lower-body fat distribution and insulin sensitivity, independent of its effects on bone. Pharmacological activation of LRP5 in adipose tissue may offer a promising strategy to prevent age-related fat redistribution and metabolic disorders. This study investigated how a protein called LRP5 affects where fat is stored in the body and how it influences metabolism (how the body uses nutrients for energy). Some people with specific changes (mutations) in the LRP5 gene tend to store more fat in their lower body, which is protective against conditions such as diabetes and heart disease, while fat in the upper body can increase health risks. To understand this, we studied individuals with different LRP5 mutations and conducted various tests and cell studies. We found that LRP5 plays a key role in directing fat to the lower body and helps fat cells respond better to insulin, independent of its role in bone health. These findings suggest that targeting LRP5 could help prevent unhealthy fat storage with aging and improve metabolic health.

OBJECTIVE: We assess diabetes risk in adulthood among adolescents with isolated glucosuria. RESEARCH DESIGN AND METHODS: Included were adolescents (16-19 years) examined before military service between 1993 and 2015. Data were linked with the Israeli National Diabetes Registry. Glucosuria was confirmed following normal renal function and glucose tolerance tests. Cox models were applied. RESULTS: The study included 1,611,467 adolescents, of whom 755 (0.05%) had glucosuria. The latter group had a higher proportion of males (75% vs. 57%) and a lower proportion of BMI ≥ 85th percentile (10.4% vs. 16.3%) compared with nonglucosuric (all P < 0.001). During follow-up, 10,328 diabetes cases were recorded with an incidence rate of 87.5 and 43.3 per 100,000 person-years for those with versus without glucosuria, respectively. Individuals with glucosuria had an adjusted hazard ratio of 2.17 (95% CI, 1.17-4.04) for diabetes. CONCLUSIONS: Glucosuria in adolescents is associated with an increased risk of early-onset diabetes.

BACKGROUND AND AIMS: Most epidemiological studies ignore long-term burden, gain and variability in body weight in assessing cardiometabolic disease risk. We investigated the associations of body mass index (BMI) trajectories measured by general practitioners with incident type 2 diabetes (T2D) and coronary artery disease (CAD). METHODS: We used electronic healthcare data from 111,615 European-ancestry participants from UK Biobank (57.1 (SD 7.8) years, 59.6 % women) with at least three BMI measurements (median trajectory period: 14.9 [interquartile range 9.5, 20.1] years). We calculated six variables capturing different long-term aspects, including i.e. burden (long-term average, area under the curve), gain (slope) and variability (standard deviation, average of the [absolute] consecutive BMI differences). The variables were used in principal component (PC) analyses and k-means clustering. Newly-derived dimensions and subgroups were used as exposures in cox-proportional hazard models. RESULTS: The BMI-trajectory indices were captured in two PCs reflecting BMI burden and BMI gain. The BMI-burden PC associated with higher T2D (hazard ratio [95 % confidence interval] per SD higher PC: 1.57 [1.55,1.60]) and CAD (1.17 [1.15,1.19]) risks, while weak or no associations were observed with the BMI-gain PC (T2D: 1.03 [1.01,1.05]; CAD: 1.01 [0.98,1.03]). Participants with the highest BMI burden, compared to those with lowest BMI burden without significant gain, had highest T2D (6.96 [6.41,7.55]) and CAD (1.57 [1.45,1.69]) risks. Both methods to capture BMI burden, gain and variability showed superior model fit compared to a single baseline BMI assessment. CONCLUSIONS: Long-term high BMI burden, irrespective of BMI gain, was a risk factor for cardiometabolic disease.