Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis.

Recent studies demonstrate that liver secretory proteins, also known as hepatokines, regulate normal development, obesity, and simple steatosis to non-alcoholic steatohepatitis (NASH) progression. Using a panel of ∼100 diverse inbred strains of mice and a cohort of bariatric surgery patients, we found that one such hepatokine, inter-trypsin inhibitor heavy chain 3 (ITIH3), was progressively lower in severe non-alcoholic fatty liver disease (NAFLD) disease states highlighting an inverse relationship between Itih3/ITIH3 expression and NAFLD severity. Follow-up animal and cell culture models demonstrated that hepatic ITIH3 overexpression lowered liver triglyceride and lipid droplet accumulation, respectively. Conversely, ITIH3 knockdown in mice increased the liver triglyceride in two independent NAFLD models. Mechanistically, ITIH3 reduced mitochondrial respiration and this, in turn, reduced liver triglycerides, via downregulated de novo lipogenesis. This was accompanied by increased STAT1 signaling and Stat3 expression, both of which are known to protect against NAFLD/NASH. Our findings indicate hepatokine ITIH3 as a potential biomarker and/or treatment for NAFLD.

Research Progress of Indole Alkaloids: Targeting MAP Kinase Signaling Pathways in Cancer Treatment.

Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted.

When diet meets genetics.

Gene expression profiling of a diverse mouse population helps to decipher how a fat-rich diet contributes to inflammatory bowel disease.

Indole alkaloids from marine resources: Understandings from therapeutic point of view to treat cancers.

Cancer is the leading cause of mortality all over the world. Scientific investigation has demonstrated that disruptions in the process of autophagy are frequently interrelated with the emergence of cancer. Hence, scientists are seeking permanent solutions to counter the deadly disease. Indole alkaloids have been extensively studied and are acknowledged to exhibit several bioactivities. The current state of disease necessitates novel pharmacophores development. In recent decades, indole alkaloids have become increasingly significant in cancer treatment and are also used as adjuvants. A substantial amount of pharmacologically active molecules come from indole alkaloids, which are widely distributed in nature. Indole alkaloids derived from marine organisms show immense potential for therapeutic applications and seem highly effective in cancer treatment. A couple of experiments have been conducted preclinically to investigate the possibility of indole alkaloids in cancer treatment. Marine-derived indole alkaloids possess the ability to exhibit anticancer properties through diverse antiproliferative mechanisms. Certain indole alkaloids, including vincristine and vinblastine, were verified in clinical trials or are presently undergoing clinical assessments for preventing and treating cancer. Indole alkaloids from marine resources hold a significant functionality in identifying new antitumor agents. The current literature highlights recent advancements in indole alkaloids that appear to be anticancer agents and the underlying mechanisms.

Mammary duct luminal epithelium controls adipocyte thermogenic programme.

Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2-7. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy.

Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

Treatment of Parkinson's Disease: Current Treatments and Recent Therapeutic Developments.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative syndrome defined by a variety of motor, cognitive, and psychomotor dysfunctions. The current pharmaceutical treatment focuses on treating the condition's symptoms. They are primarily concerned with reducing illness symptoms or avoiding dopamine metabolism. As our understanding of disease pathogenesis improves, new therapeutic approaches emerge. OBJECTIVE: This article aims to describe the standard Parkinson's medications based on symptoms and requirements. It emphasizes recent advancements in symptomatic therapy for motor indications and achievements in the research and clinical testing of medicines that promise to enable disease modification in patients with already-manifest PD. METHODS: Information for this paper was found by looking through Google Scholar and reading several research and review articles from Bentham Science, Science Direct, Elsevier, Frontiers, Taylor & Francis, and other publishers. RESULT: Parkinson's disease therapeutic interventions are now limited to symptomatic therapy, mostly in dopaminergic medications and deep brain stimulation (DBS). They have the potential to deliver great therapeutic progress, yet they can also have serious drawbacks that decrease a patient's quality of life. The progress of pluripotent stem cell therapies and genome engineering procedures has sparked renewed hope for the treatment of a wide range of human illnesses, particularly genetic abnormalities. CONCLUSION: The current Parkinson's therapy trends are successful and continually evolving, with several drugs currently undergoing clinical trials. As these new therapies constantly coming out and can be used together, they will likely change how Parkinson's disease is treated in the coming years.

Children And Adolescents With Irritable Bowel Syndrome: Treatment And Management.

BACKGROUND: Irritable bowel syndrome (IBS) is a disorder that causes stomach pain in children and adolescents. It may also impact one's quality of life. IBS is linked to gastrointestinal issues such as diarrhoea and constipation. Despite the identification of several potential pathophysiological pathways, the aetiology of IBS remained unknown. OBJECTIVE: The aim of this paper is to discuss the diagnosis, pathogenesis, case studies and treatment of Irritable bowel syndrome in children and adolescents. METHOD: This systematic review covered relevant papers from the previous ten years that were accessible in Science Direct, Elsevier, NCBI, and Web of Science related to the pathophysiology and function of pharmacological drugs such as antidepressants, antispasmodics, prokinetics, and antibiotics in children with irritable bowel syndrome. RESULT: Only a few prospective therapy techniques have been investigated in children, and even fewer of those have been demonstrated to be effective. This article presents case studies including 50-59 children, which demonstrate a favourable acceptable impact that is more effective than a placebo in terms of reducing symptoms and improving the overall quality of life in children who have irritable bowel syndrome. Furthermore, the majority of the pathophysiological explanations and treatment options discussed are based on adult studies. These major issues arose when treating paediatric IBS, and they must be addressed in order to properly treat children with IBS. Trials that focus on many combinations of pharmacological and non-pharmacological therapies seem to be more helpful. DISCUSSION: In recent years, a number of systematic reviews have been conducted to evaluate the efficacy of medication treatments in children for IBS; however, the dependability of these systematic reviews needs to be further investigated owing to the various experimental designs and levels of evidence used. This article highlights paediatric therapy options, including pharmaceutical medications such as antidepressants, antispasmodics, prokinetics, and antibiotics. The goal is to alleviate IBS symptoms while also enhancing the quality of life for children with this illness.

Sex differences in heart mitochondria regulate diastolic dysfunction.

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a "two-hit" mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

Comparative Study on the effectiveness of Glycopyrrolate/Formoterol versus Tiotropium/Formoterol in patients with Chronic Obstructive Pulmonary Disease.

Background: Chronic Obstructive Pulmonary Disease (COPD) has several implications on health, lifestyle, and economic burden. Combinational therapy using muscarinic antagonists and beta-2 agonists has long been warranted for use as maintenance therapy. A lack of studies directly comparing Glycopyrrolate/Formoterol (GFF) versus Tiotropium/Formoterol (TFF) was observed which led us to analyze the effectiveness of these combinations. Methods: In this pilot, prospective, randomized, open-label, parallel-arm, 12-week period study, 60 patients with COPD (moderate-severe) were randomized in a 1:1 ratio to receive either GFF or TFF (n = 30 each). The primary outcome was to demonstrate non-inferiority between the two groups concerning FEV1 for 12 weeks. The secondary outcome was the assessment of the ratio of FEV1/FVC and state of health evaluation by St. George's Respiratory Questionnaire (SGRQ). Results: Out of 60 participants, 58 subjects completed the study. At week 12, the mean and standard deviation value of FEV1 between groups were 1.49 ± 0.38 and 1.38 ± 0.30 (p > 0.05) and FEV1/FVC ratio were 0.67 ± 0.09 and 0.74 ± 0.08 (p < 0.01) respectively. A significant difference was observed in the FEV1 and FEV1/FVC values in comparison with baseline versus last follow up in both the groups (p < 0.01). However, no remarkable variation was identified in the FEV1 values over the two groups. The health status assessment by SGRQ showed significant improvement in both groups after the treatment. Conclusion: Non-inferiority of GFF when compared to TFF was established along with good tolerability and comparable adverse effect profile.

Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2.

We have previously suggested a central role for mitochondria in the observed sex differences in metabolic traits. However, the mechanisms by which sex differences affect adipose mitochondrial function and metabolic syndrome are unclear. Here we show that in both mice and humans, adipose mitochondrial functions are elevated in females and are strongly associated with adiposity, insulin resistance and plasma lipids. Using a panel of diverse inbred strains of mice, we identify a genetic locus on mouse chromosome 17 that controls mitochondrial mass and function in adipose tissue in a sex- and tissue-specific manner. This locus contains Ndufv2 and regulates the expression of at least 89 mitochondrial genes in females, including oxidative phosphorylation genes and those related to mitochondrial DNA content. Overexpression studies indicate that Ndufv2 mediates these effects by regulating supercomplex assembly and elevating mitochondrial reactive oxygen species production, which generates a signal that increases mitochondrial biogenesis.

Recruitment and remodeling of peridroplet mitochondria in human adipose tissue.

Beige adipocyte mitochondria contribute to thermogenesis by uncoupling and by ATP-consuming futile cycles. Since uncoupling may inhibit ATP synthesis, it is expected that expenditure through ATP synthesis is segregated to a disparate population of mitochondria. Recent studies in mouse brown adipocytes identified peridroplet mitochondria (PDM) as having greater ATP synthesis and pyruvate oxidation capacities, while cytoplasmic mitochondria have increased fatty acid oxidation and uncoupling capacities. However, the occurrence of PDM in humans and the processes that result in their expansion have not been elucidated. Here, we describe a novel high-throughput assay to quantify PDM that is successfully applied to white adipose tissue from mice and humans. Using this approach, we found that PDM content varies between white and brown fat in both species. We used adipose tissue from pheochromocytoma (Pheo) patients as a model of white adipose tissue browning, which is characterized by an increase in the capacity for energy expenditure. In contrast with control subjects, PDM content was robustly increased in the periadrenal fat of Pheo patients. Remarkably, bioenergetic changes associated with browning were primarily localized to PDM compared to cytoplasmic mitochondria (CM). PDM isolated from periadrenal fat of Pheo patients had increased ATP-linked respiration, Complex IV content and activity, and maximal respiratory capacity. We found similar changes in a mouse model of re-browning where PDM content in whitened brown adipose tissue was increased upon re-browning induced by decreased housing temperature. Taken together, this study demonstrates the existence of PDM as a separate functional entity in humans and that browning in both mice and humans is associated with a robust expansion of peri-droplet mitochondria characterized by increased ATP synthesis linked respiration.

Role of fluoxetine in pharmacological enhancement of motor functions in stroke patients: A randomized, placebo-controlled, single-blind trial.

BACKGROUND: Stroke is the primary cause of disability worldwide, the second most common cause of dementia and the third leading cause of death. Only few studies were conducted to study the role of fluoxetine in motor recovery in either ischemic or hemorrhagic stroke patients with probably less severe paresis. However, the current study evaluates both the effectiveness and safety of fluoxetine in the stroke population with a more severe motor deficit. METHODS: Patients who had acute or subacute stroke with hemiparesis and aged between 18 and 80 years with medical research council (MRC) scale score <4 were included in this randomized, Single-blind, placebo-controlled trial in 1:1 ratio to placebo or fluoxetine 20 mg/day orally for 90 days. The primary outcome measures were changes in barthel index, time taken to complete nine hole peg test and number of hand tapping movements in 30 s by the affected limb between baseline, 45th day and 90th day. The secondary outcome measure was evaluation of the drug tolerability. RESULTS: A total of 168 patients were assigned to fluoxetine (n = 84) or placebo (n = 84) group. Mean BI score significantly improved at 90th day in fluoxetine group (70.42 ± 10.56) than in placebo group (44.23 ± 8.52). Mean dexterity value decreased significantly at 90th day (2.61 ± 0.81) compared to baseline (3.98 ± 0.53) in fluoxetine group. However higher rate of decrease of mean dexterity value was seen in fluoxetine group when compared to placebo group. Mean number of hands tapping movements in 30 s increased significantly at 90th day (16.33 ± 3.58) compared to baseline (9.83 ± 2.92) in fluoxetine group. Few ADR reported during this study were dizziness, drowsiness and insomnia. CONCLUSION: The present study indicates that early prescription of fluoxetine is safe and may enhance motor function in patients presenting with severe motor impairments after stroke. However, the findings of the study should be confirmed in future controlled studies with large sample size.

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity.

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity.

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.

Liver Pyruvate Kinase Promotes NAFLD/NASH in Both Mice and Humans in a Sex-Specific Manner.

BACKGROUND & AIMS: The etiology of nonalcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate kinase (L-PK or Pklr), in NAFLD by using patient samples and mouse models. METHODS: We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis. After treatment, we measured several metabolic phenotypes including obesity, insulin resistance, dyslipidemia, liver steatosis, and fibrosis. Liver tissues were used for gene expression and immunoblotting, and liver mitochondria bioenergetics was characterized. RESULTS: In both mice and humans, L-PK expression is up-regulated in males via testosterone and is strongly associated with NAFLD severity. In a steatosis model, L-PK silencing in male mice improved glucose tolerance, insulin sensitivity, and lactate/pyruvate tolerance compared with controls. Furthermore, these animals had reduced plasma cholesterol levels and intrahepatic triglyceride accumulation. Conversely, L-PK overexpression in male mice resulted in augmented disease phenotypes. In contrast, female mice overexpressing L-PK were unaffected. Mechanistically, L-PK altered mitochondrial pyruvate flux and its incorporation into citrate, and this, in turn, increased liver triglycerides via up-regulated de novo lipogenesis and increased PNPLA3 levels accompanied by mitochondrial dysfunction. Also, L-PK increased plasma cholesterol levels via increased PCSK9 levels. On the other hand, L-PK silencing reduced de novo lipogenesis and PNPLA3 and PCSK9 levels and improved mitochondrial function. Finally, in fibrosis model, we demonstrate that L-PK silencing in male mice reduced both liver steatosis and fibrosis, accompanied by reduced de novo lipogenesis and improved mitochondrial function. CONCLUSIONS: L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Because NAFLD/nonalcoholic steatohepatitis exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.

Systems Genetics Approaches in Mouse Models of Group A Streptococcal Necrotizing Soft-Tissue Infections.

Mouse models are invaluable resources for studying the pathogenesis and preclinical evaluation of therapeutics and vaccines against many human pathogens. Infections caused by group A streptococcus (GAS, Streptococcus pyogenes) are heterogeneous ranging from mild pharyngitis to severe invasive necrotizing fasciitis, a subgroup of necrotizing soft-tissue infections (NSTIs). While several strains of mice including BALB/c, C3H/HeN, CBA/J, and C57BL/10 offered significant insights, the human specificity and the interindividual variations on susceptibility or resistance to GAS infections limit their ability to mirror responses as seen in humans. In this chapter, we discuss the advanced recombinant inbred (ARI) BXD mouse model that mimics the genetic diversity as seen in humans and underpins the feasibility to map multiple genes (genetic loci) modulating GAS NSTI. GAS produces a myriad of virulence factors, including superantigens (SAg). Superantigens are potent immune toxins that activate T cells by cross-linking T cell receptors with human leukocyte antigen class-II (HLA-II) molecules expressed on antigen-presenting cells. This leads to a pro-inflammatory cytokine storm and the subsequent multiple organ damage and shock. Inbred mice are innately refractive to SAg-mediated responses. In this chapter, we discuss the versatility of the HLA-II transgenic mouse model that allowed the biological validation of known genetic associations to GAS NSTI. The combined utility of ARI-BXD and HLA-II mice as complementary approaches that offer clinically translatable insights into pathomechanisms driven by complex traits and host genetic context and novel means to evaluate the in vivo efficiency of therapies to improve outcomes of GAS NSTI are also discussed.

Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity.

Proinflammatory macrophages are key in the development of obesity. In addition, reactive oxygen species (ROS), which activate the Fgr tyrosine kinase, also contribute to obesity. Here we show that ablation of Fgr impairs proinflammatory macrophage polarization while preventing high-fat diet (HFD)-induced obesity in mice. Systemic ablation of Fgr increases lipolysis and liver fatty acid oxidation, thereby avoiding steatosis. Knockout of Fgr in bone marrow (BM)-derived cells is sufficient to protect against insulin resistance and liver steatosis following HFD feeding, while the transfer of Fgr-expressing BM-derived cells reverts protection from HFD feeding in Fgr-deficient hosts. Scavenging of mitochondrial peroxides is sufficient to prevent Fgr activation in BM-derived cells and HFD-induced obesity. Moreover, Fgr expression is higher in proinflammatory macrophages and correlates with obesity traits in both mice and humans. Thus, our findings reveal the mitochondrial ROS-Fgr kinase as a key regulatory axis in proinflammatory adipose tissue macrophage activation, diet-induced obesity, insulin resistance and liver steatosis.

Sex-specific metabolic functions of adipose Lipocalin-2.

OBJECTIVE: Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and has also been associated with several cardiometabolic traits in both mouse and human studies. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males. METHODS: Using adeno-associated viral vectors we expressed LCN2 in either adipose or liver in a tissue specific manner on the background of a whole-body Lcn2 knockout or wildtype mice. Metabolic phenotypes including body weight, body composition, plasma and liver lipids, glucose homeostasis, insulin resistance, mitochondrial phenotyping, and metabolic cage studies were monitored. RESULTS: We studied the genetics of LCN2 expression and associated clinical traits in both males and females in a panel of 100 inbred strains of mice (HMDP). The natural variation in Lcn2 expression across the HMDP exhibits high heritability, and genetic mapping suggests that it is regulated in part by Lipin1 gene variation. The correlation analyses revealed striking tissue dependent sex differences in obesity, insulin resistance, hepatic steatosis, and dyslipidemia. To understand the causal relationships, we examined the effects of expression of LCN2 selectively in liver or adipose. On a Lcn2-null background, LCN2 expression in white adipose promoted metabolic disturbances in females but not males. It acted in an autocrine/paracrine manner, resulting in mitochondrial dysfunction and an upregulation of inflammatory and fibrotic genes. On the other hand, on a null background, expression of LCN2 in liver had no discernible impact on the traits examined despite increasing the levels of circulating LCN2 more than adipose LCN2 expression. The mechanisms underlying the sex-specific action of LCN2 are unclear, but our results indicate that adipose LCN2 negatively regulates its receptor, LRP2 (or megalin), and its repressor, ERα, in a female-specific manner and that the effects of LCN2 on metabolic traits are mediated in part by LRP2. CONCLUSIONS: Following up on our population-based studies, we demonstrate that LCN2 acts in a highly sex- and tissue-specific manner in mice. Our results have important implications for human studies, emphasizing the importance of sex and the tissue source of LCN2.