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Nakajo-Nishimura syndrome/proteasome-associated autoinflammatory syndrome (NNS/PRAAS) is a hereditary autoinflammatory disease. Clinically, NNS/PRAAS is characterized by periodic fever, skin rash, partial lipo-muscular atrophy, and joint contractures. Among PRAAS, NNS, is genetically characterized by a homozygous founder variant in the proteasome subunit beta type 8 (PSMB8) gene encoding an inducible proteasome component β5i. To establish an in vivo animal model recapitulating NNS/PRAAS, we generated mice harboring this founder variant. In Psmb8 G201V/G201V mice, the immature β5i subunit was increased and 20S proteasome activity was significantly reduced in the spleen, whereas 26S proteasome activity was preserved and ubiquitin accumulation was not apparent. Compared with wild-type mice, Psmb8 G201V/G201V mice exhibited a shortened lifespan and, as they aged, showed less weight gain and adipocyte shrinkage with interstitial macrophage infiltration and cytokine production/activation. The mutant mice also manifested significantly lower proportion of T cells in total splenocytes, with higher CD4 + and lower CD8 + T cell proportions. Psmb8 G201V/G201V mice shared some characteristic autoinflammatory and progeroid phenotypes as observed in NNS/PRAAS patients, although their proteasome defect pattern was distinct. Thus, Psmb8 G201V/G201V mice should be useful not only for investigation of NNS/PRAAS pathogenesis but also for examining the clinical effect of candidate drugs on NNS/PRAAS and related diseases.

Lipoatrophy, the localized loss of subcutaneous fat, is a rare complication of insulin therapy that persists despite advancements in insulin formulations and delivery systems. This case report describes a 58-year-old woman with type 1 diabetes mellitus who developed considerable abdominal wall lipoatrophy 4 months after initiating insulin pump therapy. Management included changing the infusion cannula type, rotating insertion sites, and switching insulin analogues, resulting in stabilization and complete improvement of lipoatrophy over 16 months. A diagnostic and management algorithm is proposed, incorporating site rotation, cannula and insulin type modifications, and potential adjunctive therapies including topical sodium cromoglycate and corticosteroids.

Lupus panniculitis is a chronic subtype of cutaneous lupus erythematosus. It typically presents as tender, firm subcutaneous nodules on the proximal extremities, face, and/or trunk and can leave behind disfiguring scarring or lipoatrophy in the post-inflammatory phase. When a patient presents with physical or emotional distress secondary to lupus panniculitis-induced lipoatrophy, there are variable data on treatment with autologous fat transfer and injectable fillers. We present the case of a 37-year-old female presenting with lipoatrophy of the right cheek, after 2 years of quiescent disease, undergoing successful volume restoration with injectable hyaluronic acid filler.

Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g., Igfbp1 , Cd36 and Ccl2 ) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression. Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare—Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Lipodystrophy alters insulin absorption, potentially leading to unpredictable hypoglycemia and inadequate glycemic control. Although the problem is long known, it continues to persist and remains neglected, particularly among diabetic patients in developing countries. This study evaluated its magnitude and different contributing factors. This study aimed to assess the prevalence of lipodystrophy, and their contributing factors among patients receiving insulin therapy in three selected hospitals of Northwest Ethiopia. A cross-sectional study was conducted from April 5 to September 30, 2023, at the University of Gondar, Tibebe ghion and Debre Markos Comprehensive Specialized Hospitals. Standardized physical examinations were used to assess the presence of lipodystrophy and data on demographic characteristics, clinical characteristics, and drug related characteristics were used for analysis. Logistic regression was used to identify factors associated with lipodystrophy. Among participants, 54.3% had type 1 diabetes mellitus. The larger part of study participants (71.5%) reported having diabetes mellitus for over five years. Insulin-induced lipodystrophy was observed in 225 cases (53.1%). Grade 2 lipohypertrophy was the most common type (52.7%), marked by significant fat thickening, while Grade 3 lipoatrophy was rare (1.8%). The abdomen was the most affected injection site (36.5%), followed by multiple sites (32%). Failure to rotate (AOR = 1.8, p-value 0.004), needle reuse, glycemic control (AOR = 2.15, p-value 0.019), and insulin dosage per kg (AOR = 2.1, p-value 0.001) were found to have an association with lipodystrophy. The study revealed a high prevalence of lipodystrophy among diabetic patients using insulin injections, highlighting the need for greater attention to ensure comprehensive diabetes care.

Background. Fat gain after antiretroviral therapy (ART) occurs, and its association with protease inhibitors (PIs) is unclear. Methods. Peripheral and central fat depots and lean mass were measured using standardized and centrally read abdominal CT scans and whole-body dual-energy absorptiometry scans over a 96-week period in human immunodeficiency virus (HIV)–infected treatment-naive participants. The patients were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) in ACTG A5260s, a substudy of A5257. Within arm changes were assessed with signed-rank tests. The 96-week percentage changes in fat and lean mass in the 2 PI arms were not different, thus the PI arms were combined and compared to the RAL arm. Associations between baseline biomarkers and changes in body composition were assessed. All analyses used linear regression models. Results. 328 patients were randomized (90% male, 44% white non-Hispanic). The median age was 36 years, HIV-1 RNA 4.6 log 10 copies/mL, and CD4 349 cells/μL. Overall, at week 96, increases in limb fat (13.4%), subcutaneous (19.9%) and visceral abdominal fat (25.8%), trunk fat (18%), and lean mass (1.8%) were apparent (P< .001 for changes within each arm). Changes for all fat and lean outcomes were not different between the PI arms or between the RAL and the combined PI arms. Higher baseline HIV-1 RNA levels were associated with greater gains in peripheral and central fat. Conclusions. In treatment-naive participants initiating ART with TDF/FTC, no differences in lean mass and regional fat were found with RAL when compared with ATV/r or DRV/r over 96 weeks. Clinical Trials Registration. NCT00811954 and NCT00851799.

Adipose tissues are highly dynamic in response to environmental temperature changes. During aging, subcutaneous white adipose tissues (WAT) decreases, yet whether this atrophy exacerbates cold stress and triggers systemic aging remains unclear. Here we show that adipocyte-specific expression of the Lmna G609G mutation in male mice leads to progressive WAT atrophy, accelerates aging, and shortens lifespan, whereas female mice remain unaffected. This lipoatrophy exacerbates cold stress, triggering cyclooxygenase-2 (COX-2) upregulation in WAT, and increased prostaglandin E 2 production, which mediates the elevation of core body temperature (CBT). Inhibiting COX-2 by celecoxib or thermotherapy by housing the lipoatrophic mice at 26 °C (normally 22 °C) ameliorates cold stress, restores CBT, reduces aging features, and extends lifespan. Our findings reveal that subcutaneous WAT atrophy and subsequent CBT elevation induced by chronic mild cold stress are drivers of systemic aging in male mice, identifying thermotherapy as a potential regimen for progeria. Lipoatrophy is a feature of premature aging, including in a rare genetic form of premature aging caused by a mutation in A-type lamin gene ( Lmna ). Here the authors report that adipocyte-specific expression of the Lmna G609G mutation leads to progressive white adipose tissue atrophy, accelerated aging and shortens lifespan mediated by cyclooxygenase-2 in male mice, whereas female mice remain unaffected.