Dual Role of Caspase 8 in Adipocyte Apoptosis and Metabolic Inflammation.

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional nonapoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes. Here, we examined the pleiotropic role of caspase 8 in adipocytes and obesity-associated insulin resistance. Caspase 8 expression was increased in adipocytes from mice and humans with obesity and insulin resistance. Treatment of 3T3-L1 adipocytes with caspase 8 inhibitor Z-IETD-FMK decreased both death receptor-mediated signaling and targets of nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling. We generated novel adipose tissue and adipocyte-specific caspase 8 knockout mice (aP2Casp8-/- and adipoqCasp8-/-). Both males and females had improved glucose tolerance in the setting of high-fat diet (HFD) feeding. Knockout mice also gained less weight on HFD, with decreased adiposity, adipocyte size, and hepatic steatosis. These mice had decreased adipose tissue inflammation and decreased activation of canonical and noncanonical NF-κB signaling. Furthermore, they demonstrated increased energy expenditure, core body temperature, and UCP1 expression. Adipocyte-specific activation of Ikbkb or housing mice at thermoneutrality attenuated improvements in glucose tolerance. These data demonstrate an important role for caspase 8 in mediating adipocyte cell death and inflammation to regulate glucose and energy homeostasis. ARTICLE HIGHLIGHTS: Caspase 8 is increased in adipocytes from mice and humans with obesity and insulin resistance. Knockdown of caspase 8 in adipocytes protects mice from glucose intolerance and weight gain on a high-fat diet. Knockdown of caspase 8 decreases Fas signaling, as well as canonical and noncanonical nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling in adipose tissue. Improved glucose tolerance occurs via reduced activation of NF-κB signaling and via induction of UCP1 in adipocytes.

Cbl-b modulated TrkA ubiquitination and function in the dorsal root ganglion of mice.

Casitas B-lineage lymphoma b (Cbl-b) is one of the E3 ubiquitin ligases that ubiquitinate Tropomyosin-related kinase A (TrkA), a key nerve growth factor receptor involved in the pathological pain. Here we found that Cbl-b was abundant in dorsal root ganglion (DRG) neurons of mice and co-localized with TrkA. Ubiquitination of TrkA by Cbl-b exerted a tonic negative control over the protein level of TrkA. Knockdown of Cbl-b caused TrkA accumulation in DRGs and evoked mechanical and heat hypersensitivity in intact mice. Our data showed that knee osteoarthritis induced by destabilization of the medial meniscus (DMM) led to the dissociation of Cbl-b with TrkA in DRG neurons, which impaired the ability of Cbl-b to ubiquitinate TrkA and served as an important mechanism to cause TrkA-dependent pain sensitization. Viral expression of constitutively active Cbl-b in DRGs of osteoarthritic mice effectively repressed TrkA protein level and more importantly, alleviated mechanical allodynia and heat hyperalgesia. Viral delivery of Cbl-b through intra-articular route generated a similar analgesic action. These data suggested that ubiquitination of TrkA by Cbl-b might represent an effective way to treat the osteoarthritic pain.

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice.

Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone apolipoprotein E (ApoE)-null mice (L-Igf1-/-ApoE-/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice and their littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18 to 19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection from atherosclerosis in females was associated with increased subcutaneous adiposity and with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating interleukin-6 (IL-6) levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis, potentially through athero-promoting effects of adipose tissue-derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.

Metabolic Role of PTEN in Insulin Signaling and Resistance.

Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified. Through the use of a variety of models, such as tissue-specific knockout (KO) mice and in vitro cell cultures, PTEN's role in regulating insulin action has been elucidated across many cell types. Herein, we will review the recent advancements in the understanding of PTEN's metabolic functions in each of the tissues and cell types that contribute to regulating systemic insulin sensitivity and discuss how PTEN may represent a promising therapeutic strategy for treatment or prevention of T2D.

Artificial Total Disc Replacement Versus Fusion for Lumbar Degenerative Disc Disease: An Update Systematic Review and Meta-Analysis.

AIM: To conduct an updated systematic review and meta-analysis to compare the efficacy and safety between total disc replacement (TDR) and fusion surgery for lumbar degenerative disc disease (LDDD). MATERIAL AND METHODS: We comprehensively searched meta-analyses comparing TDR with fusion through the PubMed, Embase, and Cochrane Library databases. Only randomized controlled trials (RCTs) were selected and collected. The end of the retrieval time was June 2017. Two authors independently extracted the data from the studies after assessing their quality. The statistical software STATA version 12.0 was used to analyze the data. RESULTS: A total of seven RCTs (1706 patients) were included in our analysis. The patients in the TDR group had significantly improved. A greater percentage of these patients were satisfied with the surgery concerning Oswestry disability index, visual analog scale score, and complication rate. In addition, the clinical success in the TDR group was greater than that in the fusion group. Meanwhile, the TDR group had shorter operative time and hospital stay. However, there was no clinical significance regarding blood loss, work status, and reoperation rate between the two groups. CONCLUSION: Our current updated meta-analysis suggests that TDR could be an alternative treatment for LDDD, since it yielded better clinical success and patient satisfaction, shorter hospital stay and operative time, less pain, and lower complication rates than lumbar fusion.

Three-dimensional reconstructions in spine and screw trajectory simulation on 3D digital images: a step by step approach by using Mimics software.

There is a rapidly increasing amount of literature outlining the use of three-dimensional (3D) reconstruction and printing technologies in recent years. However, precise instructive articles which describe step-by-step methods of reconstructing 3D images from computed tomography (CT) or magnetic resonance imaging (MRI) remain limited. To address these issues, this article describes a detailed protocol which will allow the reader to easily perform the 3D reconstruction in their future research, to allow investigation of the appropriate surgical anatomy and allow innovative designs of novel screw fixation techniques or pre-operative surgical planning.