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Obesity leads to the development of nonalcoholic fatty liver disease (NAFLD) and associated alterations to the plasma proteome. To elucidate the underlying changes associated with obesity, we performed liquid chromatography-tandem mass spectrometry in the liver and plasma of obese leptin-deficient ob/ob mice and integrated these data with publicly available transcriptomic and proteomic datasets of obesity and metabolic diseases in preclinical and clinical cohorts. We quantified 7173 and 555 proteins in the liver and plasma proteomes, respectively. The abundance of proteins related to fatty acid metabolism were increased, alongside peroxisomal proliferation in ob/ob liver. Putatively secreted proteins and the secretory machinery were also dysregulated in the liver, which was mirrored by a substantial alteration of the plasma proteome. Greater than 50% of the plasma proteins were differentially regulated, including NAFLD biomarkers, lipoproteins, the 20S proteasome, and the complement and coagulation cascades of the immune system. Integration of the liver and plasma proteomes identified proteins that were concomitantly regulated in the liver and plasma in obesity, suggesting that the systemic abundance of these plasma proteins is regulated by secretion from the liver. Many of these proteins are systemically regulated during type 2 diabetes and/or NAFLD in humans, indicating the clinical importance of liver-plasma cross talk and the relevance of our investigations in ob/ob mice. Together, these analyses yield a comprehensive insight into obesity and provide an extensive resource for obesity research in a prevailing model organism., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15 ® , on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

Background: Type 2 diabetes and obesity are often seen concurrently with skeletal muscle wasting, leading to further derangements in function and metabolism. Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass. The aim of this study was to investigate the effects of modified UCN2 peptides as a pharmaceutical therapy to counteract the loss of skeletal muscle mass associated with obesity and casting immobilization., Methods: High-fat-fed mice (C57Bl/6J; 26 weeks old) and ob/ob mice (11 weeks old) were injected daily with a PEGylated (Compound A) and non-PEGylated (Compound B) modified human UCN2 at 0.3 mg/kg subcutaneously for 14 days. A separate group of chow-fed C57Bl/6J mice (12 weeks old) was subjected to hindlimb cast immobilization and, after 1 week, received daily injections with Compound A. In vivo functional tests were performed to measure protein synthesis rates and skeletal muscle function. Ex vivo functional and molecular tests were performed to measure contractile force and signal transduction of catabolic and anabolic pathways in skeletal muscle., Results: Skeletal muscles (extensor digitorum longus, soleus, and tibialis anterior) from high-fat-fed mice treated with Compound A were ~14% heavier than muscles from vehicle-treated mice. Chronic treatment with modified UCN2 peptides altered the expression of structural genes and transcription factors in skeletal muscle in high-fat diet-induced obesity including down-regulation of Trim63 and up-regulation of Nr4a2 and Igf1 (P < 0.05 vs. vehicle). Signal transduction via both catabolic and anabolic pathways was increased in tibialis anterior muscle, with increased phosphorylation of ribosomal protein S6 at Ser 235/236 , FOXO1 at Ser 256 , and ULK1 at Ser 317 , suggesting that UCN2 treatment modulates protein synthesis and degradation pathways (P < 0.05 vs. vehicle). Acutely, a single injection of Compound A in drug-naïve mice had no effect on the rate of protein synthesis in skeletal muscle, as measured via the surface sensing of translation method, while the expression of Nr4a3 and Ppargc1a4 was increased (P < 0.05 vs. vehicle). Compound A treatment prevented the loss of force production from disuse due to casting. Compound B treatment increased time to fatigue during ex vivo contractions of fast-twitch extensor digitorum longus muscle. Compound A and B treatment increased lean mass and rates of skeletal muscle protein synthesis in ob/ob mice., Conclusions: Modified human UCN2 is a pharmacological candidate for the prevention of the loss of skeletal muscle mass associated with obesity and immobilization., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)