COVID-19 Vaccine Uptake in Undocumented Latinx Patients Presenting to the Emergency Department.

This cross-sectional study examines COVID-19 infection status, vaccination uptake, and perceptions about the vaccine among Latinx patients presenting to the emergency department in California.

FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition.

The protein kinases IKKε and TBK1 are activated in liver and fat in mouse models of obesity. We have previously demonstrated that treatment with the IKKε/TBK1 inhibitor amlexanox produces weight loss and relieves insulin resistance in obese animals and patients. While amlexanox treatment caused a transient reduction in food intake, long-term weight loss was attributable to increased energy expenditure via FGF21-dependent beiging of white adipose tissue (WAT). Amlexanox increased FGF21 synthesis and secretion in several tissues. Interestingly, although hepatic secretion determined circulating levels, it was dispensable for regulating energy expenditure. In contrast, adipocyte-secreted FGF21 may have acted as an autocrine factor that led to adipose tissue browning and weight loss in obese mice. Moreover, increased energy expenditure was an important determinant of improved insulin sensitivity by amlexanox. Conversely, the immediate reductions in fasting blood glucose observed with acute amlexanox treatment were mediated by the suppression of hepatic glucose production via activation of STAT3 by adipocyte-secreted IL-6. These findings demonstrate that amlexanox improved metabolic health via FGF21 action in adipocytes to increase energy expenditure via WAT beiging and that adipocyte-derived IL-6 has an endocrine role in decreasing gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.

Surgical rotator cuff muscle biopsies: are they representative of overall muscle quality?

BACKGROUND: Current research on human rotator cuff pathology relies on superficial biopsy specimens. It is unclear whether these biopsies are representative of overall muscle quality. The purpose of this study is to use magnetic resonance imaging with iterative decomposition of echoes of asymmetric length sequencing to investigate variability of fatty infiltration within the supraspinatus and infraspinatus muscle. METHODS: We retrospectively identified 45 patients who underwent arthroscopic rotator cuff repair with preoperative iterative decomposition of echoes of asymmetric length imaging completed. The supraspinatus and infraspinatus were segmented on 4 consecutive slices, including the scapular Y, 2 slices medial, and 1 slice lateral. Intramuscular fat was measured in multiple regions for both supraspinatus (whole muscle, anterior, posterior, superficial band, anterior band, and posterior band) and infraspinatus (whole muscle, superior, inferior, superficial band, superior band, and inferior band). Comparisons of intramuscular fat were determined with Wilcoxon sign-rank tests. Analysis of variance was used to compare between the 4 consecutive slices. Significance was defined as P < .05. RESULTS: Magnetic resonance imaging showed 31 full-thickness supraspinatus tears, 10 partial-thickness supraspinatus tears, and 4 intact supraspinatus tendons and 3 full-thickness infraspinatus tears, 2 partial-thickness infraspinatus tears, and 40 intact infraspinatus tendons. The anterior supraspinatus contained significantly higher fat content than the posterior supraspinatus (7.4% ± 7.4% vs. 5.4% ± 5.7%, P = .003). The superior and inferior halves of the infraspinatus were not different from each other (P = .11). The superficial band did not differ from the whole muscle in both supraspinatus (P = .14) and infraspinatus (P = .20). However, the anterior band of the supraspinatus had significantly more fat than the posterior band (8.2% ± 9.3% vs. 5.0% ± 5.7%, respectively, P < .0001), and the superior band of the infraspinatus had significantly more fat than the inferior band (5.2% ± 4.8% vs. 4.2% ± 5.3%, respectively, P = .03). There was no difference between all 4 medial and lateral slices in the supraspinatus (P = .92) and infraspinatus (P = .90). CONCLUSION: Fat fractions within the supraspinatus and infraspinatus demonstrate significant spatial variability that may influence interpretation of local biopsy samples. Future biopsy studies may benefit from multiple samples between different specific locations.

Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3.

Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of ß-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.

Design, synthesis, and biological activity of substituted 2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as inhibitors of the inflammatory kinases TBK1 and IKKε for the treatment of obesity.

The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R7 and R8 A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R7 cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.

Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKKε and Reveal Mechanisms for Selective Inhibition.

Chronic low-grade inflammation is a hallmark of obesity, which is a risk factor for the development of type 2 diabetes. The drug amlexanox inhibits IκB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) to promote energy expenditure and improve insulin sensitivity. Clinical studies have demonstrated efficacy in a subset of diabetic patients with underlying adipose tissue inflammation, albeit with moderate potency, necessitating the need for improved analogs. Herein we report crystal structures of TBK1 in complex with amlexanox and a series of analogs that modify its carboxylic acid moiety. Removal of the carboxylic acid or mutation of the adjacent Thr156 residue significantly reduces potency toward TBK1, whereas conversion to a short amide or ester nearly abolishes the inhibitory effects. IKKε is less affected by these modifications, possibly due to variation in its hinge that allows for increased conformational plasticity. Installation of a tetrazole carboxylic acid bioisostere improved potency to 200 and 400 nM toward IKKε and TBK1, respectively. Despite improvements in the in vitro potency, no analog produced a greater response in adipocytes than amlexanox, perhaps because of altered absorption and distribution. The structure-activity relationships and cocrystal structures described herein will aid in future structure-guided inhibitor development using the amlexanox pharmacophore for the treatment of obesity and type 2 diabetes.

ERRγ Preserves Brown Fat Innate Thermogenic Activity.

Brown adipose tissue (BAT) adaptively transfers energy from glucose and fat into heat by inducing a gene network that uncouples mitochondrial electron transport. However, the innate transcription factors that enable the rapid adaptive response of BAT are unclear. Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor for maintaining BAT identity. ERRγ is selectively expressed in BAT versus WAT, in which, in the absence of PGC1α, it drives a signature transcriptional network of thermogenic and oxidative genes in the basal (i.e., thermoneutral) state. Mice lacking ERRγ in adipose tissue (ERRγKO mice) display marked downregulation of BAT-selective genes that leads to a pronounced whitening of BAT. Consistent with the transcriptional changes, the thermogenic capacity of ERRγKO mice is severely blunted, such that they fail to survive an acute cold challenge. These findings reveal a role for ERRγ as a critical thermoneutral maintenance factor required to prime BAT for thermogenesis.

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.