Exercise training and cold exposure trigger distinct molecular adaptations to inguinal white adipose tissue.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well established. Here, we tested the hypothesis that inguinal white adipose tissue (iWAT) adaptations are critical for these beneficial effects and determined the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improves glucose tolerance, while cold-exposed iWAT transplantation shows no such benefit. Compared to training, cold leads to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting the thermogenic capacity of iWAT. In contrast, only training increases extracellular space and vesicle transport proteins, and only training upregulates proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.

Supplementing Best Care with Specialized Rehabilitation Treatment in Parkinson's Disease: A Retrospective Study by Different Expert Centers.

Background: This is a retrospective longitudinal study comparing 374 patients with Parkinson's disease (PD) who were treated in centers offering a specialized program of enhanced rehabilitation therapy in addition to expert outpatient care to 387 patients with PD, who only received expert outpatient care at movement disorders centers in Italy. Methods: The data are from subjects recruited in the Parkinson's Outcome Project (POP) at six Italian centers that are part of a multicenter collaboration for care quality improvement (the Fresco Network). The effects were measured with a baseline and a follow-up clinical evaluation of the Timed-Up-and-Go test (TUG), Parkinson's Disease Questionnaire (PDQ-39), and Multidimensional Caregiver Strain Index (MCSI), the number of falls and hospitalizations for any cause. We used a generalized linear mixed model with the dependent variables being the response variable, which included the covariates demographics, evaluation, and treatment variables. Results: We found that the subjects who underwent specialized enhanced rehabilitation had a better motor outcome over time than those who were managed by expert neurologists but had participated in community programs for exercise and other allied health interventions. The greatest effects were seen in patients in the early stages of the disease with a high amount of vigorous exercise per week in the last six months. Similar effects were seen for PDQ39, MCSI, the number of falls, and hospitalization. Conclusions: Long-term benefits to motor function and the quality of life in patients with PD and burden reduction in their caregivers can be achieved through a systematic program of specialized enhanced rehabilitation interventions.

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Hyposmia correlates with axial signs and gait disorder in Parkinson's disease: an Italian Olfactory Identification Test study.

BACKGROUND: Olfactory dysfunction is a non-motor symptom and an important biomarker of Parkinson's disease (PD) because of its high prevalence (> 90%). Whether hyposmia correlates with motor symptoms is unclear. In the present study, we aim to investigate the relationship between olfactory impairment with both motor and non-motor features and disease variables (disease duration, stage, and severity). METHODS: One-hundred fifty-four PD patients were evaluated. Odor identification ability was tested using Italian Olfactory Identification Test (IOIT). A comprehensive spectrum of motor and non-motor features was assessed. Cognitive function was investigated through MMSE. Patients were divided into 3 different clinical phenotypes using UPDRS-III: tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT). RESULTS: Three of the 33 IOIT items were most frequently misidentified: basil (74.3%), coffee (66.9%), and mushroom (59.6%). Hyposmia was found in 93%. Hyposmic patients were older than controls (p = 0.01). Hoehn & Yahr (H&Y) score of 2 or greater was associated with higher probability of being hyposmic (OR = 5.2, p = 0.01). IOIT score did not significantly differ between TDT, ART, and MXT of analyzed PD patients. Performance to IOIT inversely correlated with age (p < 0.01), disease duration (p = 0.01), and H&Y score of 2 or higher (p < 0.01). Clinical features that associated with higher IOIT score were freezing of gait (FOG) (p < 0.001) and camptocormia (p < 0.05). CONCLUSIONS: In our cohort, IOIT scores showed a positive correlation with axial motor signs, but not with non-motor symptoms. IOIT may be a useful tool not only for supporting PD diagnosis but also for providing prognostic information about motor function.

Exercise Training and Cold Exposure Trigger Distinct Molecular Adaptations to Inguinal White Adipose Tissue.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well-established. We tested the hypothesis that adaptations to inguinal white adipose tissue (iWAT) are critical for these beneficial effects by determining the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improved glucose tolerance, while cold-exposed iWAT transplantation showed no such benefit. Compared to training, cold led to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting iWAT's thermogenic capacity. In contrast, only training increased extracellular space and vesicle transport proteins, and only training upregulated proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.

Moderate-intensity endurance training improves late phase ß-cell function in adults with type 2 diabetes.

Physical activity is important for type 2 diabetes treatment, yet the underlying mechanisms for these beneficial effects of exercise are not fully understood. Here, we investigated the effects of exercise training on biphasic ß-cell insulin secretory function, a key factor regulating blood glucose. Adults with type 2 diabetes (7F/3M, age 49 ± 5 years, BMI 30 ± 3 kg/m2) completed a 10-week moderate-intensity exercise program and multiple components of glucose homeostasis were measured. Training improved glycemic control, insulin sensitivity, and processing of proinsulin-to-insulin. Training increased late phase ß-cell function by 38% (p = 0.01), which was correlated with changes in VO2peak suggesting training response-dependent effects. Ras-Responsive Element Binding Protein 1 (RREB1) concentrations, a protein postulated to increase type 2 diabetes risk, were inversely correlated with increases in training-induced late-phase disposition index, consistent with an inhibitory role of RREB1 on insulin secretion. Moderate-intensity exercise training improves late-phase ß-cell function and glycemic control in adults with type 2 diabetes.

CSF neurochemical profile and cognitive changes in Parkinson's disease with mild cognitive impairment.

Pathophysiological substrate(s) and progression of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) are still matter of debate. Baseline cerebrospinal fluid (CSF) neurochemical profile and cognitive changes after 2 years were investigated in a retrospective series of PD-MCI (n = 48), cognitively normal PD (PD-CN, n = 40), prodromal Alzheimer's disease (MCI-AD, n = 25) and cognitively healthy individuals with other neurological diseases (OND, n = 44). CSF biomarkers reflecting amyloidosis (Aß42/40 ratio, sAPPα, sAPPß), tauopathy (p-tau), neurodegeneration (t-tau, NfL, p-NfH), synaptic damage (α-syn, neurogranin) and glial activation (sTREM2, YKL-40) were measured. The great majority (88%) of PD-MCI patients was A-/T-/N-. Among all biomarkers considered, only NfL/p-NfH ratio was significantly higher in PD-MCI vs. PD-CN (p = 0.02). After 2 years, one-third of PD-MCI patients worsened; such worsening was associated with higher baseline levels of NfL, p-tau, and sTREM2. PD-MCI is a heterogeneous entity requiring further investigations on larger, longitudinal cohorts with neuropathological verification.

Exercise training remodels inguinal white adipose tissue through adaptations in innervation, vascularization, and the extracellular matrix.

Inguinal white adipose tissue (iWAT) is essential for the beneficial effects of exercise training on metabolic health. The underlying mechanisms for these effects are not fully understood, and here, we test the hypothesis that exercise training results in a more favorable iWAT structural phenotype. Using biochemical, imaging, and multi-omics analyses, we find that 11 days of wheel running in male mice causes profound iWAT remodeling including decreased extracellular matrix (ECM) deposition and increased vascularization and innervation. We identify adipose stem cells as one of the main contributors to training-induced ECM remodeling, show that the PRDM16 transcriptional complex is necessary for iWAT remodeling and beiging, and discover neuronal growth regulator 1 (NEGR1) as a link between PRDM16 and neuritogenesis. Moreover, we find that training causes a shift from hypertrophic to insulin-sensitive adipocyte subpopulations. Exercise training leads to remarkable adaptations to iWAT structure and cell-type composition that can confer beneficial changes in tissue metabolism.

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.