Mechanisms by which the IKK-related Kinases Affect Energy Expenditure.

Numerous studies have implicated an inflammatory link between obesity and type 2 diabetes. We applied a multidisciplinary approach spanning from in vivo animal physiology to in vitro cell culture and biochemistry to address the role of obesity-related inflammation in adipose tissue. The inhibitor of κB kinase β (IKKβ) has previously been linked to insulin resistance. High-fat diet dramatically increased protein and kinase activity levels of the two noncanonical IKK family members, IKKε and TBK1, in adipose tissue. Genetic ablation of IKKε or pharmacologic inhibition of IKKε and TBK1, using the selective protein kinase inhibitor amlexanox, resulted in many metabolic improvements, including reduced weight gain in mice on a high fat diet. The improvements in IKKε knockout and amlexanox-treated mice on a high fat diet were correlated with increased energy expenditure, core body temperature, adipogenesis, and the proton uncoupling protein, UCP1 protein levels in adipose tissue. Studies with 3T3-L1 adipocytes elucidated the mechanism by which IKKε and TBK1 regulate cAMP and β-adrenergic signaling in 3T3-L1 adipocytes. Expression of IKKε in 3T3-L1 adipocytes decreased UCP1 expression in response to β-adrenergic stimulation. The rate of lipolysis, levels of cAMP, and phosphorylation of PKA substrates such as hormone sensitive lipase (HSL) were also diminished in response to isoproterenol or forskolin by overexpression of IKKε or TBK1 in 3T3-L1 adipocytes. IKKε and TBK1 are induced by inflammatory stimuli, such as tumor necrosis α (TNFα) and Poly(I:C), and blockade of these kinases reversed the diminution of β-adrenergic signaling, cAMP, and lipolysis. The reduction of cAMP levels in 3T3-L1 adipocytes expressing IKKε or TBK1 was reversed by the phosphodiesterase 3B inhibitor, zardaverine. IKKε and TBK1 were found to bind to and phosphorylate PDE3B at serine 318, resulting in its activation and 14-3-3β binding. These studies suggest that reduced cAMP production through phosphorylation and activation of PDE3B by IKKε and TBK1 is responsible for mediating the effects of IKKε and TBK1 in adipocytes.PHDMolecular & Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107243/1/jonmow_1.pd

Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1.

Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKε and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKε and TBK1 may contribute to the repression of energy expenditure during obesity. DOI: http://dx.doi.org/10.7554/eLife.01119.001

Higher Rates of Residual Postoperative Instability after Anterior Cruciate Ligament Reconstruction in Female Patients : A Systematic Review of Level II Studies

To compare revision rates and residual postoperative instability after anterior cruciate ligament (ACL) reconstruction based on biological sex. A systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Embase, MEDLINE, and Cochrane library databases were queried from database inception through October 2022. Level I and II prospectively-enrolling human clinical studies that compared revision rates and physical examination of postoperative stability after ACL reconstruction between male and female patients were included. Outcomes were stratified by patient sex and quantitatively compared using a χ 2 test. Study quality was assessed using the MINORS criteria. Four studies consisting of 406 patients (50% males) with a mean age of 25 years (range, 13.9-62 years) were identified. Mean follow-up time was 34.4 months (range, 22-60 months). Hamstring tendon autografts were used in 62% of ACL reconstructions in males and in 65% of ACL reconstructions in females, whereas bone-patellar tendon-bone autografts were used in 38% and 35% of procedures in males and females, respectively. A residual positive Lachman test result was more frequently reported among females compared to males (5.8% vs 0.6%; P = 0.03). No significant difference in revision rates or residual pivot-shift on examination was observed between males and females (P = 0.38 and P = 0.08, respectively). Female patients undergoing ACL reconstruction have higher reported rates of residual anterior instability with Lachman than male patients. However, no sex-based differences were identified with residual pivot-shift on examination or rate of revision ACL surgery. II; Systematic Review of level II studies

The protein kinase IKKepsilon regulates energy balance in obese mice

Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here, we show that high-fat diet can increase NF-kappaB activation in mice, which leads to a sustained elevation in level of IkappaB kinase epsilon (IKKepsilon) in liver, adipocytes, and adipose tissue macrophages. IKKepsilon knockout mice are protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKepsilon knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKepsilon may represent an attractive therapeutic target for obesity, insulin resistance, diabetes, and other complications associated with these disorder

The protein kinase IKKepsilon regulates energy balance in obese mice

Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here, we show that high-fat diet can increase NF-kappaB activation in mice, which leads to a sustained elevation in level of IkappaB kinase epsilon (IKKepsilon) in liver, adipocytes, and adipose tissue macrophages. IKKepsilon knockout mice are protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKepsilon knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKepsilon may represent an attractive therapeutic target for obesity, insulin resistance, diabetes, and other complications associated with these disorder

Higher Rates of Residual Postoperative Instability after Anterior Cruciate Ligament Reconstruction in Female Patients: A Systematic Review of Level II Studies

Purpose: To compare revision rates and residual postoperative instability after anterior cruciate ligament (ACL) reconstruction based on biological sex. Methods: A systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Embase, MEDLINE, and Cochrane library databases were queried from database inception through October 2022. Level I and II prospectively-enrolling human clinical studies that compared revision rates and physical examination of postoperative stability after ACL reconstruction between male and female patients were included. Outcomes were stratified by patient sex and quantitatively compared using a χ2 test. Study quality was assessed using the MINORS criteria. Results: Four studies consisting of 406 patients (50% males) with a mean age of 25 years (range, 13.9-62 years) were identified. Mean follow-up time was 34.4 months (range, 22-60 months). Hamstring tendon autografts were used in 62% of ACL reconstructions in males and in 65% of ACL reconstructions in females, whereas bone-patellar tendon-bone autografts were used in 38% and 35% of procedures in males and females, respectively. A residual positive Lachman test result was more frequently reported among females compared to males (5.8% vs 0.6%; P = 0.03). No significant difference in revision rates or residual pivot-shift on examination was observed between males and females (P = 0.38 and P = 0.08, respectively). Conclusion: Female patients undergoing ACL reconstruction have higher reported rates of residual anterior instability with Lachman than male patients. However, no sex-based differences were identified with residual pivot-shift on examination or rate of revision ACL surgery. Level of Evidence: II; Systematic Review of level II studies

Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit.

UNLABELLED: Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment. SIGNIFICANCE: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown