The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to β-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5β, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.

The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.

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BackgroundAngiotensin I-converting enzyme (ACE) has two functional N- and C-domain active centers that display differences in the metabolism of biologically-active peptides including the hemoregulatory tetrapeptide, Ac-SDKP, hydrolysed preferentially by the N domain active center. Elevated Ac-SDKP concentrations are associated with reduced tissue fibrosis.ResultsWe identified a patient of African descent exhibiting unusual blood ACE kinetics with reduced relative hydrolysis of two synthetic ACE substrates (ZPHL/HHL ratio) suggestive of the ACE N domain center inactivation. Inhibition of blood ACE activity by anti-catalytic mAbs and ACE inhibitors and conformational fingerprint of blood ACE suggested overall conformational changes in the ACE molecule and sequencing identified Ser333Trp substitution in the N domain of ACE. In silico analysis demonstrated S333W localized in the S1 pocket of the active site of the N domain with the bulky Trp adversely affecting binding of ACE substrates due to steric hindrance. Expression of mutant ACE (S333W) in CHO cells confirmed altered kinetic properties of mutant ACE and conformational changes in the N domain. Further, the S333W mutant displayed decreased ability (5-fold) to cleave the physiological substrate AcSDKP compared to wild-type ACE.Conclusions and SignificanceA novel Ser333Trp ACE mutation results in dramatic changes in ACE kinetic properties and lowered clearance of Ac-SDKP. Individuals with this mutation (likely with significantly increased levels of the hemoregulatory tetrapeptide in blood and tissues), may confer protection against fibrosis.

BACKGROUND: New virtual resources ("novel resources") have been incorporated into medical education. No recent large studies about their use and perception among internal medicine (IM) residents exist. OBJECTIVE: Characterize the use and perceived helpfulness of educational resources. DESIGN: Nationwide survey from December 2019 to March 2020. PARTICIPANTS: IM residents in the USA. MAIN MEASURES: Residents were surveyed on their use and their perceived helpfulness of resources for both attaining general medical knowledge and for point-ofcare (POC) learning. Traditional resources included board review resources, clinical experience, digital clinical resources (e.g., UpToDate), journal articles, pocket references, professional guidelines, textbooks, and residency curricula. Novel resources included Twitter, video streaming platforms (e.g., YouTube), online blogs, podcasts, and Wikipedia. KEY RESULTS: We had 662 respondents from 55 residency programs across 26 states. On average, residents used 9 total resources (7 traditional and 2 novel). Digital clinical resources and clinical experience were used by all residents and found helpful by the highest percentage of residents (96% and 94%, respectively). Journal articles were next (used by 90%), followed by board review resources and residency curricula (both used by 85%). Their perceived helpfulness varied, from 90% for board review resources, to 66% for journal articles and 64% for residency curricula, the lowest perceived helpfulness of any traditional resource. Podcasts and video streaming platforms were used as frequently as textbooks (58-59%), but were rated as helpful more frequently (75% and 82% vs 66%, respectively). CONCLUSIONS: Digital clinical resources, video streaming platforms, and podcasts were perceived as helpful, underscoring the importance of ensuring their integration into medical education to complement clinical experience and other traditional resources which remain highly valued by residents. IMPORTANCE: Our findings can inform residency programs as they transition to virtual curricula in the wake of the COVID-19 pandemic.