Background: Obesity-related diseases result from accumulation of lipids in nonadipose tissues. Results: Mutations in 167 yeast genes confer fatty acid sensitivity. Loss of yeast and mammalian ARV1 results in pronounced lipid hypersensitivity, lipoapoptosis, and reduced triglyceride synthesis. Conclusion: 75 evolutionarily conserved components of obesity-related disorders were identified. Significance: Understanding lipid sensitivity may lead to treatment of numerous human metabolic diseases.

Type 2 diabetes is marked by progressive β-cell failure, leading to loss of β-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to β-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of β-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting β-cells, we performed a high-throughput screen of 20,876 compounds in the rat insulinoma cell line INS-1E in the presence of elevated glucose and palmitate. We found 312 glucolipotoxicity-protective small molecules (1.49% hit rate) capable of restoring INS-1E viability, and we focused on 17 with known biological targets. 16 of the 17 compounds were kinase inhibitors with activity against specific families including but not limited to cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2). 7 of the 16 kinase inhibitors were PI3K inhibitors. Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity.

<p> There is an ongoing need to understand the molecular mechanisms  responsible for generating protective immunity to aid rational vaccine  design. Various vaccine administration sites contain unique  distributions of resident immune populations and other influencing  factors in the microenvironment that may alter adaptive immune response  generation. Typically, vaccination is administered intramuscularly or  subcutaneously, however, many infectious diseases invade their hosts  through the mucosal membranes, including the respiratory tract. Thereby,  administering vaccines through the mucosa may represent a more natural  infection route and establish specialised immune responses.To date, the  importance of vaccine administration site remains unclear and thus  should be investigated to understand whether specific local vaccination  sites are of relevance in achieving desired immune responses. </p> <p> The main goal of vaccination is to activate antigen-presenting cells  (APCs), such as dendritic cells (DCs), to then prime the adaptive immune  response. DCs lie at the interface between innate and adaptive  immunity, thus, to take up antigen they patrol body sites commonly  invaded by pathogens, such as the skin and lung. Upon antigen uptake,  DCs migrate to the draining lymph node to interact with T cells,  resulting in CD4+ T cell activation and differentiation into distinct T  helper subsets. Due to their remarkable ability to sense their  environment and interact with pathogens, the context of DC activation  instructs the adaptive immune response to react in the manner most  suitable to eliminate the particular pathogen. Therefore, DCs are  central to gaining a better understanding of the events involved in  initiating an immune response.</p> <p>  The aim of this investigation was to compare the immune cell composition  and response in the skin and lung microenvironments. To address this, I  used the novel vaccine adjuvant, αGalCer, which specifically activates  innate-like natural killer T (NKT) cells and DCs, leading to  peptide-specific T cell responses. APC activation and adaptive immune  response generation were assessed in the skin and lung. I discovered  that there was a greater proportion of T cells specialised to help B  cells in the skin, compared to an enriched effector T cell phenotype in  the lung. Additionally, the lung immune response was found to depend  specifically on DC1 subset activation and the cytokine IFN-γ, likely  produced by NKT cells upon activation, thus providing a mechanism for  differential immune response generation in the skin and lung. These  findings indicated that the tissue microenvironment could influence the  adaptive immune response generated by vaccination, which is of great  importance in the context of vaccine design. </p>

The “Thin on the Outside Fat on the Inside” TOFI_Asia study found Asian Chinese to be more susceptible to Type 2 Diabetes (T2D) compared to European Caucasians matched for gender and body mass index (BMI). This was influenced by degree of visceral adipose deposition and ectopic fat accumulation in key organs, including liver and pancreas, leading to altered fasting plasma glucose, insulin resistance, and differences in plasma lipid and metabolite profiles. It remains unclear how intra-pancreatic fat deposition (IPFD) impacts TOFI phenotype-related T2D risk factors associated with Asian Chinese. Cow’s milk whey protein isolate (WPI) is an insulin secretagogue which can suppress hyperglycemia in prediabetes. In this dietary intervention, we used untargeted metabolomics to characterize the postprandial WPI response in 24 overweight women with prediabetes. Participants were classified by ethnicity (Asian Chinese, n=12; European Caucasian, n=12) and IPFD (low IPFD &lt; 4.66%, n=10; high IPFD ≥ 4.66%, n=10). Using a cross-over design participants were randomized to consume three WPI beverages on separate occasions; 0 g (water control), 12.5 g (low protein, LP) and 50 g (high protein, HP), consumed when fasted. An exclusion pipeline for isolating metabolites with temporal (T0-240mins) WPI responses was implemented, and a support vector machine-recursive feature elimination (SVM-RFE) algorithm was used to model relevant metabolites by ethnicity and IPFD classes. Metabolic network analysis identified glycine as a central hub in both ethnicity and IPFD WPI response networks. A depletion of glycine relative to WPI concentration was detected in Chinese and high IPFD participants independent of BMI. Urea cycle metabolites were highly represented among the ethnicity WPI metabolome model, implicating a dysregulation in ammonia and nitrogen metabolism among Chinese participants. Uric acid and purine synthesis pathways were enriched within the high IPFD cohort’s WPI metabolome response, implicating adipogenesis and insulin resistance pathways. In conclusion, the discrimination of ethnicity from WPI metabolome profiles was a stronger prediction model than IPFD in overweight women with prediabetes. Each models’ discriminatory metabolites enriched different metabolic pathways that help to further characterize prediabetes in Asian Chinese women and women with increased IPFD, independently.