ARMC5 selectively degrades SCAP-free SREBF1 and is essential for fatty acid desaturation in adipocytes.

SREBF1 plays the central role in lipid metabolism. It has been known that full-length SREBF1 that did not associate with SCAP (SCAP-free SREBF1) is actively degraded, but its molecular mechanism and its biological meaning remain unclear. ARMC5-CUL3 complex was recently identified as E3 ubiquitin ligase of full-length SREBF.

Novel humanized anti-PcrV monoclonal antibody COT-143 protects mice from lethal infection via inhibition of toxin translocation by the type III secretion system.

Treatment of infection is challenging due to its intrinsic and acquired antibiotic resistance. As the number of current therapeutic options for infections is limited, developing novel treatments against the pathogen is an urgent clinical priority. The suppression of virulence of could be a new therapeutic option, and the type III secretion system (T3SS), which enables the bacteria to translocate various kinds of toxins into host cells and inhibits cellular functions, is considered as one possible target.

The role of oxidative stress, glucocorticoid receptor and ARMC5 in lipid metabolism.

Lipid metabolism includes lipogenesis, lipolysis, and cholesterol metabolism and it exerts a wide range of biological effects. We previously found novel roles of adipocyte oxidative stress in diet-induced obesity, adipocyte glucocorticoid receptor in Cushing syndrome, and ARMC5 in adrenocortical cells. Using genetically modified mice in which oxidative stress was eliminated or augmented specifically in adipose tissues, we have been able to elucidate that obesity-induced oxidative stress inhibited healthy adipose expansion and ameliorated insulin sensitivity.

HSP47 levels determine the degree of body adiposity.

Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences.

ARMC5-CUL3 E3 ligase targets full-length SREBF in adrenocortical tumors.

Inactivating mutations of ARMC5 are responsible for the development of bilateral macronodular adrenal hyperplasia (BMAH). Although ARMC5 inhibits adrenocortical tumor growth and is considered a tumor-suppressor gene, its molecular function is poorly understood. In this study, through biochemical purification using SREBF (SREBP) as bait, we identified the interaction between SREBF and ARMC5 through its Armadillo repeat.

Ketone body 3-hydroxybutyrate enhances adipocyte function.

Ketone bodies, including 3HBA, are endogenous products of fatty acid oxidation, and Hmgcs2 is the first rate-limiting enzyme of ketogenesis. From database analysis and in vivo and in vitro experiments, we found that adipose tissue and adipocytes express Hmgcs2, and that adipocytes produce and secrete 3HBA. Treatment with 3HBA enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors in adipose tissue in vivo and in adipocytes in vitro, accompanied by reduced ROS levels.

Glutamine deficiency induces lipolysis in adipocytes.

Glutamine is the most abundant amino acid in the body, and adipose tissue is one of the glutamine-producing organs. Glutamine has important and unique metabolic functions; however, its effects in adipocytes are still unclear. 3T3-L1 adipocytes produced and secreted glutamine dependent on glutamine synthetase, but preadipocytes did not.

Laparoscopic resection of aortocaval paraganglioma diagnosed by serial increase in urinary metanephrines after bilateral adrenalectomy in a patient with multiple endocrine neoplasia type 2A.

Introduction: Although bilateral pheochromocytoma is prevalent in patients with multiple endocrine neoplasia type 2, extra-adrenal tumors rarely occur in the aortocaval area.

Case Presentation: A 35-year-old man with multiple endocrine neoplasia type 2A ( codon Cys634Arg mutation) underwent bilateral adrenalectomy for metachronous pheochromocytoma. After bilateral adrenalectomy, urinary metanephrines decreased below the measurement sensitivity.

Coincidence of Large Adrenal Cyst and Prominent Hyporeninemic Hyperaldosteronism.

A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism.

Oral Contraceptive Disturbed the Recovery of the Adrenal Function after Adrenalectomy in Cushing Syndrome.

Estrogen is known to increase exogenous corticosteroid levels. In this case, a 27-year-old Japanese woman was referred to our hospital for examination of an adrenal tumor and was diagnosed with Cushing syndrome. Resection of the tumor resulted in secondary adrenal insufficiency.

Marked Hypergastrinemia with G-cell Hyperplasia in Two Autoimmune Gastritis Patients.

Gastrin regulates gastric acid secretion, and gastrin secretion itself is regulated by the negative feedback system of gastric acidity. Autoimmune gastritis (AG) is a disease where parietal cells are destroyed, resulting in decreased acid production and an elevated serum gastrin level. We herein report 2 AG cases with marked hypergastrinemia (>5,000 pg/mL).

Adipocyte GR Inhibits Healthy Adipose Expansion Through Multiple Mechanisms in Cushing Syndrome.

In Cushing syndrome, excessive glucocorticoids lead to metabolic disturbances, such as insulin resistance, adipocyte hypertrophy, and liver steatosis. In vitro experiments have highlighted the importance of adipocyte glucocorticoid receptor (GR), but its metabolic roles in vivo have not been fully elucidated in Cushing syndrome. In this study, using clinical samples from patients with Cushing syndrome and adipocyte-specific GR knockout (AGRKO) mice, we investigated the roles of adipocyte GR and its clinical relevance in Cushing syndrome.

Impact of MR on mature adipocytes in high-fat/high-sucrose diet-induced obesity.

Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high-fat/high-sucrose diet.

Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes.

Sodium/glucose cotransporter 2 (SGLT2) inhibitor improves systemic glucose metabolism. To clarify the effect of dapagliflozin, we performed gene expression microarray and metabolomic analyses of murine adipose tissue. Three groups of mice were used; non-diabetic control KK mice (KK), diabetic KKAy mice (KKAy), and KKAy mice treated with dapagliflozin (KKAy + Dapa).

Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression of SREBF1-Mediated Lipogenic Pathway.

Recent studies have emphasized the association of adipose oxidative stress (Fat reactive oxygen species [ROS]) with the pathogenesis of metabolic disorders in obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivo remain unclear because no mouse model has been available in which oxidative stress is manipulated by targeting adipocytes. In this research, we generated two models of Fat ROS-manipulated mice and evaluated the metabolic features in diet-induced obesity.

Impact of dexamethasone concentration on cartilage tissue formation from human synovial derived stem cells in vitro.

Human synovial mesenchymal stem cells (hSMSCs) are a promising cell source for cartilage regeneration because of their superior chondrogenic potential in vitro. This study aimed to further optimize the conditions for inducing chondrogenesis of hSMSCs, focusing on the dose of dexamethasone in combination with transforming growth factor-β3 (TGFβ3) and/or bone morphogenetic protein-2 (BMP2). When hSMSCs-derived aggregates were cultured with TGFβ3, dexamethasone up to 10 nM promoted chondrogenesis, but attenuated it with heterogeneous tissue formation when used at concentrations over than 100 nM.

Novel insights into histone modifiers in adipogenesis.

Recently, it has been progressively recognized that gene expression is regulated by histone methylation status, which is dynamically modulated by histone methyltransferases (HMTs) and histone demethylases (HDMs). In the past decade, many HMTs and HDMs were identified and their biological and biochemical functions have been characterized. As with other cells, several HMTs and HDMs are known to be indispensable for appropriate differentiation of adipocytes from mesenchymal stem cells.

Epigenetic regulation of adipogenesis by PHF2 histone demethylase.

PHF2 is a JmjC family histone demethylase that removes the methyl group from H3K9me2 and works as a coactivator for several metabolism-related transcription factors. In this study, we examined the in vivo role of PHF2 in mice. We generated Phf2 floxed mice, systemic Phf2 null mice by crossing Phf2 floxed mice with CMV-Cre transgenic mice, and tamoxifen-inducible Phf2 knockout mice by crossing Phf2 floxed mice with Cre-ERT2 transgenic mice.

PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B.

Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2-ARID5B.

KIAA1718 is a histone demethylase that erases repressive histone methyl marks.

The methylation states of histone lysine residues are regarded as significant epigenetic marks governing transcriptional regulation. A number of histone demethylases containing a jumonji C (JmjC) domain have been recognized; however, their properties remain to be investigated. Here, we show that KIAA1718, a PHF2/PHF8 subfamily member, possesses histone demethylase activity specific for H3K9 and H3K27, transcriptionally repressive histone marks.

Human catalase gene is regulated by peroxisome proliferator activated receptor-gamma through a response element distinct from that of mouse.

Oxidative stress has been implicated as a causal role in atherosclerosis, microvascular complications of diabetes as well as in beta cell failure in type 2 diabetes. PPARgamma agonists not only improve insulin sensitivity but also eliminate oxidative stress. In mouse, catalase, a major antioxidant enzyme, is directly regulated by PPARgamma through two PPARgamma binding elements in its promoter.

Competitive binding of musclin to natriuretic peptide receptor 3 with atrial natriuretic peptide.

Musclin is a novel skeletal muscle-derived secretory factor that was isolated by our group. Musclin contains a region homologous to natriuretic peptides (NPs). This study investigated the interaction between musclin and NP receptors (NPRs).

Identification of a novel distal enhancer in human adiponectin gene.

Adiponectin is exclusively expressed in adipose tissue and secreted from adipocytes, and shows anti-diabetic and anti-atherogenic properties. However, the precise transcriptional mechanism of adiponectin remains elusive. In this study, the 5' flanking promoter region of human adiponectin gene was analyzed using UCSC genome browser, and a 10 390-bp fragment, containing an evolutionally conserved region among species, was investigated.

Adipose expression of catalase is regulated via a novel remote PPARgamma-responsive region.

In adipose tissue of obese mice, the expression of catalase, an anti-oxidant enzyme, significantly decreases, which may cause insufficient elimination of hydrogen peroxide, but it does not in liver or skeletal muscle. However, the precise regulatory mechanism of catalase expression in adipocytes has not been fully defined. Here, we demonstrated that adipose tissues highly expressed catalase on the level comparable to liver and kidney, and treatment of mice with PPARgamma agonist significantly enhanced catalase expression in adipose tissue but not in liver.