脂肪萎縮症

Both excessive white adipose tissue (WAT) in obesity and insufficient WAT in lipodystrophy disrupt metabolic homeostasis. Although a vicious cycle between WAT dysfunction and gut dysbiosis is known to drive insulin resistance in obesity, whether lipodystrophy impairs gut function and contributes to glucose dysregulation remains unclear. Using adipocyte-specific MDM2 knockout (Adipo-MDM2-KO) mice as a model of lipodystrophy, we identified a direct role of WAT in maintaining intestinal and gut microbiota homeostasis. Progressive adipose tissue loss in Adipo-MDM2-KO mice caused multiple intestinal abnormalities, including gut microbiota dysbiosis, altered microbial metabolism, impaired intestinal barrier integrity, defective immunoglobulin A (IgA) responses, and endotoxemia. These defects were largely reversed by transplantation of healthy subcutaneous WAT (sWAT). Moreover, fecal microbiota transplantation from Adipo-MDM2-KO mice into C57BL/6J recipients reproduced intestinal defects and glucose intolerance, whereas microbiota depletion in Adipo-MDM2-KO mice largely rescued intestinal abnormalities and partially restored glucose homeostasis. Furthermore, sWAT-secreted adipokines, including extracellular vesicles, directly modulated the abundance and growth of specific gut bacterial communities. Multi-omics analyses further linked lipodystrophy-induced microbiota and metabolomic alterations to systemic endotoxemia and impaired glucose metabolism. Altogether, our findings reveal a critical WAT-gut-microbiota axis in the regulation of intestinal homeostasis and host glucose metabolism.

Obesity is a chronic, relapsing disease that is defended by complex biologic regulatory mechanisms, and is defined by excessive or abnormal adipose tissue that impairs health. Among people with HIV (PWH), the epidemiology of body weight has shifted dramatically in the modern antiretroviral therapy (ART) era, with obesity now replacing wasting and lipodystrophy as dominant body-composition phenotypes. Excess adiposity in PWH arises from overlapping influences: persistent immune activation, ART-specific effects on adipose tissue, and the same environmental factors driving the global obesity epidemic. The consequences include insulin resistance, dyslipidemia, cardiovascular disease, and fatty liver disease, which now constitute the leading causes of morbidity and mortality in this population. This review summarizes the pathophysiology, epidemiology, and management of obesity in PWH, emphasizing mechanisms that link ART exposure to altered adipose biology and metabolic risk. Effective care requires an integrated approach combining behavioral, pharmacologic, and procedural strategies within multidisciplinary HIV programs. Recognizing obesity as a chronic, treatable disease reframes management away from lifestyle blame toward durable metabolic control. In contemporary HIV care, the goal extends beyond viral suppression to encompass the prevention of cardiometabolic disease and preservation of long-term health.

BACKGROUND AND AIMS: Elevated heart rate (HR) is an established cardiovascular risk marker, yet its ambulatory profile across body mass index (BMI) strata in hypertensive patients remains incompletely characterized. We investigated the association between BMI and office and ambulatory HR, and explored heart rate variability (HRV), in a large real-world cohort of hypertensive outpatients. METHODS AND RESULTS: In this retrospective observational study 10,003 consecutive adult outpatients undergoing standardized office and ambulatory blood pressure monitoring (ABPM) were stratified by BMI (<25, 25-29, 30-34, and ≥35 kg/m2). Mean HR was assessed at office and during 24-h, daytime, and night-time periods. HRV was estimated as the coefficient of variation (CV%) of ambulatory HR. Multivariable models were adjusted for age, sex, systolic blood pressure, and negative chronotropic therapies. Increasing BMI was associated with a graded rise in HR across all settings (P < 0.001). Compared with normal-weight individuals, patients with BMI ≥35 kg/m2 showed higher office HR (79.6 vs 75.7), higher 24-h HR (76.7 vs 72.5), and higher night-time HR (70.8 vs 65.3 bpm) (all P < 0.001). These associations remained significant after multivariable adjustment and were consistent in both treated and untreated patients. Restricted cubic spline analyses suggested a non-linear relationship between BMI and ambulatory HR. HRV was lower in severe obesity, particularly during the 24-h and night-time periods, although associations were modest in continuous analyses. CONCLUSIONS: In hypertensive outpatients, severe obesity is independently associated with higher office and ambulatory HR across the 24-h period, defining a distinct chronotropic phenotype. Alterations in ambulatory HRV appear less pronounced.

Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipid and energy homeostasis, mediate hormone production, produce inflammation signaling, while also participating in numerous biological processes and activities. Dysregulation of LD homeostasis is linked to various diseases, such as lipodystrophy, obesity, type 2 diabetes (T2D), cardiovascular diseases (CVD), metabolic dysfunction-associated steatotic liver disease (MASLD), neuronal diseases, and among others. The core of LDs consists of neutral lipids, including triacylglycerol (TAG), cholesteryl esters (CE), and retinyl esters (RE), which are encircled by a monolayer of phospholipid membrane decorated with a subset of LD proteins, both resident as well as dynamic, that vary in different cells, tissues, organs, and organisms. Over the past two decades, together with technological advances, significant achievements have been made in understanding LD biology, including their lifecycle: such as biogenesis, growth/expansion, fusion, and degradation, as well as their diversity and heterogeneity, under both physiological and pathological conditions. In this review, we summarize the current knowledge and methodologies of LD biology in animal cells, and also provide guiding questions, hopefully bringing new directions for future study of LDs and for potential therapeutic treatments for LD-related human diseases.

BACKGROUND: Primary laminopathies are a heterogeneous group of rare diseases caused by nuclear lamina dysfunction due to pathogenic LMNA variants. However, despite their ubiquitous expression, LMNA variants have rarely been linked to chronic kidney disease (CKD). Here, we systematically investigate clinical implications and functional underpinnings of a distinct LMNA missense variant (lamin A/C p.(Arg349Trp)) that has sporadically been found in patients with a complex phenotype including lipodystrophy, proteinuria, and focal segmental glomerulosclerosis (FSGS). METHODS: In clinical and functional terms, we compare lamin A/C Arg349Trp with missense changes at Arg482, the most common hotspot residue for type 2 familial partial lipodystrophy (FPLD2). In particular, we assess renal endpoints in corresponding patient cohorts and investigate disease-associated alterations in vitro. RESULTS: In contrast to FPLD2 patients, individuals with lamin A/C Arg349Trp experience high-grade proteinuria and a rapid decline of glomerular filtration rate with kidney failure at a median age of 43 years. Mechanistically, we demonstrate that Arg349Trp associates with an abrogation of the structural interaction between lamin A/C and nucleoporin 155, nuclear pore complex aggregation, and an alteration of TGF-β1-dependent signaling. CONCLUSIONS: While patients with Lamin A/C Arg482 missense changes are at very low risk for progressive CKD, patients harboring Arg349Trp show nephrotic range proteinuria and kidney failure in midlife. Hence, high-grade proteinuric kidney disease is genotype-specific and patients with the Arg349Trp substitution require early renoprotective intervention to potentially halt progression and prevent kidney failure. FUNDING: German Research Foundation, project IDs 502928386, 445703531, and grants HA 9779/2-1, HA 6908/4-1, HA 6908/7-1, HA 6908/8-1, HA 6908/12-1.