An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models.

AIMS/HYPOTHESIS: Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood. METHODS: We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). RESULTS: Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. CONCLUSIONS/INTERPRETATION: The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

Sports injury and illness incidence in the PyeongChang 2018 Olympic Winter Games: a prospective study of 2914 athletes from 92 countries.

OBJECTIVE: To describe the incidence of injuries and illnesses sustained during the XXIII Olympic Winter Games, hosted by PyeongChang on 9-25 February 2018. METHODS: We recorded the daily number of athlete injuries and illnesses (1) through the reporting of all National Olympic Committee (NOC) medical teams and (2) in the polyclinic and medical venues by the PyeongChang 2018 medical staff. RESULTS: In total, 2914 athletes (1210 women, 42%; 1704 men, 58%) from 92 NOCs were observed for occurrence of injury and illness. NOC and PyeongChang 2018 medical staff reported 376 injuries and 279 illnesses, equalling 12.6 injuries and 9.4 illnesses per 100 athletes over the 17-day period. Altogether, 12% of the athletes incurred at least one injury and 9% at least one illness. The injury incidence was highest in ski halfpipe (28%), snowboard cross (26%), ski cross (25%), snowboard slopestyle (21%) and aerials (20%), and lowest in Nordic combined, biathlon, snowboard slalom, moguls and cross-country skiing (2%-6%). Of the 376 injuries recorded, 33% and 13% were estimated to lead to ≥1 day and >7 days of absence from sport, respectively. The highest incidences of illness were recorded in biathlon (15%), curling (14%), bobsleigh (14%) and snowboard slalom (13%). Thirty per cent of the illnesses were expected to result in time loss, and 70% affected the respiratory system. Women suffered 61% more illnesses than men. CONCLUSION: Overall, 12% of the athletes incurred at least one injury during the Games and 9% an illness, incidences that are similar to the Olympic Winter Games of 2010 and 2014.

Dysregulation of mitophagy in carcinogenesis and tumor progression.

The mitochondrial role in carcinogenesis and cancer progression is an area of active research, with many unresolved questions. Various aspects of altered mitochondrial function have been implicated in tumorigenesis and tumor progression, including mitochondrial dysfunction, a metabolic switch to aerobic glycolysis, and dysregulation of mitophagy. Mitophagy is a highly specific quality control process which eliminates dysfunctional mitochondria and promotes mitochondrial turnover, and is involved in the adaptation to nutrient stress by controlling mitochondrial mass. The dysregulation of mitochondrial turnover has both a positive and negative role in cancer. This review will begin with a basic overview of the molecular mechanisms of mitophagy, and highlight recent trends in mitophagy from cancer studies. We will conclude this review by discussing areas of research in normal mitophagy that have yet to be explored in the context of cancer such as mitochondrial proteases, the mitochondrial unfolded protein response, and mitokine action. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Regeneration of thyroid follicles from primordial cells in a murine thyroidectomized model.

The functional unit of the thyroid gland, the thyroid follicle, dynamically responds to various stimuli to maintain thyroid hormone homeostasis. However, thyroid follicles in the adult human thyroid gland have a very limited regenerative capacity following partial resection of the thyroid gland. To gain insight into follicle regeneration in the adult thyroid gland, we observed the regeneration processes of murine thyroid follicles after partial resection of the lower third of the thyroid gland in 10-week-old male C57BL/6 mice. Based on sequential observation of the partially resected thyroid lobe, we found primitive follicles forming in the area corresponding to the central zone of the intact lateral thyroid lobe. The primitive thyroid follicles were multiciliated and had coarsely vacuolated cytoplasm and large vesicular nuclei. Consistently, these primitive follicular cells did not express the differentiation markers paired box gene-8 and thyroid transcription factor-1 (clone SPT24), but were positive for forkhead box protein A2 and leucine-rich repeat-containing G-protein-coupled receptor 4/GPR48. Follicles newly generated from the primitive follicles had clear or vacuolar cytoplasm with dense, darkly stained nuclei. At day 21 after partial thyroidectomy, the tall cuboidal follicular epithelial cells had clear or vacuolar cytoplasm, and the intraluminal colloid displayed pale staining. Smaller activated follicles were found in the central zone of the lateral lobe, whereas larger mature follicles were located in the peripheral zone. Based on these observations, we propose that the follicle regeneration process in the partially resected adult murine thyroid gland associated with the appearance of primitive follicular cells may be a platform for the budding of differentiated follicles in mice.

Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure.

AIM/HYPOTHESIS: Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown. METHODS: We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane. RESULTS: Crif1(beta-/-) mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1(beta-/-) mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1(beta-/-) mice. CONCLUSIONS/INTERPRETATION: Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1(beta-/-) mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.

Dysregulation of Parkin-mediated mitophagy in thyroid Hürthle cell tumors.

Abnormal accumulation of defective mitochondria is the hallmark of oncocytes, which are frequently observed in thyroid Hürthle cell lesions. Autophagy is an essential cellular catabolic mechanism for the degradation of dysfunctional organelles and has been implicated in several human diseases. It is yet unknown how autophagic turnover of defective mitochondria in Hürthle cell tumors is regulated. We characterized the expression patterns of molecular markers including Beclin1, LC3, PINK1 and Parkin, which are required for autophagy or mitophagy, in human oncocytic lesions of the thyroid. To undertake mechanistic studies, we investigated autophagy and mitophagy using XTC.UC1 cells, the only in vitro model of Hürthle cell tumors. Beclin1 and LC3 were highly expressed in oncocytes of Hürthle cell tumors. XTC.UC1 showed autophagic responses to starvation and rapamycin treatment, whereas they displayed ineffective activation of mitophagy, which is triggered by the coordinated action of PINK1 and Parkin in response to CCCP. This resulted in a decreased turnover of abnormal mitochondria. The mechanisms underlying defective mitophagy and mitochondrial turnover were investigated by genetic analysis of the PARK2 gene in XTC.UC1 and Hürthle cell tumor tissues. XTC.UC1 and several tumors harbored the V380L mutation, resulting in dysfunctional autoubiquitination and decreased E3 ligase activity. Consistently, oncocytes in Hürthle cell tumors displayed comparable expression of PINK1 but decreased Parkin expression in comparison to normal thyrocytes. The introduction of wild-type Parkin sensitized XTC.UC1 to death induced by CCCP. This study provides a possible etiological basis for oncocytic formation in heterogeneous Hürthle cell tumors through insufficient mitophagy leading to ineffective turnover of aberrant mitochondria caused by dysfunctional Parkin-mediated pathways of mitochondria quality control.

The indole derivative NecroX-7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with cirrhosis and hepatocellular carcinoma. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play key roles in the development of the disease. However, the therapeutic target of NASH has not been fully defined and new treatments are needed. We investigated the protective effects of the antioxidant indole-derived NecroX-7 in a NASH mouse model using leptin-deficient ob/ob and methionine- and choline-deficient (MCD) diet-fed ob/ob mice. METHODS: Six-week-old male mice were divided into three groups: ob/+ mice, ob/ob mice treated with vehicle and ob/ob mice treated daily with NecroX-7 (20 mg/kg) for 4 weeks. To study the effects of NecroX-7 in a fibrosis model, NASH was induced by feeding ob/ob mice an MCD diet. The effects of NecroX-7 on NASH progression were evaluated using biochemical, histological and molecular markers. RESULTS: NecroX-7-treated ob/ob mice had a marked decrease in serum aspartate aminotransferase and alanine transaminase compared with vehicle-treated controls. Interestingly, hepatic steatosis and lipid peroxidation were significantly improved by NecroX-7 treatment. NecroX-7 inhibited tert-butylhydroperoxide- and H2 O2 -induced mitochondrial ROS/RNS in primary hepatocytes and attenuated mitochondrial dysfunction in vitro and in vivo. Furthermore, NecroX-7-treated mice exhibited fewer infiltrating macrophages and reduced hepatic tumour necrosis factor-alpha expression. Hepatic fibrosis in MCD-fed ob/ob mice was significantly decreased by NecroX-7 treatment. CONCLUSIONS: NecroX-7 treatment improved hepatic steatosis and fibrosis in murine NASH models. These effects occurred through the suppression of whole-cell ROS/RNS and inflammatory responses and suggest that NecroX-7 has a potential therapeutic benefit in steatohepatitis.

Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases.

Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPRmt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPRmt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.

Combined Intrathoracic and Abdominal Splenosis.

BACKGROUND Splenosis refers to autotransplantation of splenic tissue after splenic injury or splenectomy, most frequently occurring in the abdominal and pelvic cavities. Thoracic splenosis is a rare condition associated with a history of simultaneous rupture of the spleen and diaphragm resulting from trauma. To the best of our knowledge, only a limited number of cases have been reported for combined intrathoracic and abdominal splenosis. CASE REPORT We present a case of a 50-year-old man with a history of splenectomy and left nephrectomy 15 years ago due to an accident, who had experienced chest pain for the past month. A 1-cm focal pleural thickening in the left posterior pleura was revealed on the chest computed tomography (CT) scan. We found this to be suspicious for a solitary fibrous tumor. Based on this information, surgery was performed for tumor removal, and the pathologic examination confirmed splenic tissues. The patient was then discharged without any complications. Further abdominopelvic CT showed several contrast-enhanced lesions, suggestive of intraperitoneal splenosis. CONCLUSIONS We would like to emphasize the importance of thorough history-taking to avoid misdiagnosis and unnecessary procedures with respect to the rarity of splenosis. Moreover, appropriate use of diagnostic tools, including radionuclide imaging studies, is recommended to establish an accurate diagnosis of thoracic splenosis.

Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice.

BACKGROUND: Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss, the biological characteristics of the relationship between muscle and bone remain obscure. We showed that muscle atrophy caused by skeletal muscle-specific CR6-interacting factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, leading to low bone mass. METHODS: MKO mice with lower muscle OxPhos were fed a normal chow or high-fat diet and then evaluated for muscle mass and function, and bone mineral density. Immunophenotyping of BM immune cells was also performed. BM transcriptomic analysis was used to identify key factors regulating bone mass in MKO mice. To determine the effects of BM-derived CXCL12 (C-X-C motif chemokine ligand 12) on regulation of bone homeostasis, a variety of BM niche-resident cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune cell samples from 14 patients with hip fracture were investigated to examine the association between muscle function and BM inflammation. RESULTS: MKO mice exhibited significant reductions in both muscle mass and expression of OxPhos subunits but increased transcription of mitochondrial stress response-related genes in the extensor digitorum longus (P < 0.01). MKO mice showed a decline in grip strength and a higher drop rate in the wire hanging test (P < 0.01). Micro-computed tomography and von Kossa staining revealed that MKO mice developed a low mass phenotype in cortical and trabecular bone (P < 0.01). Transcriptomic analysis of the BM revealed that mitochondrial stress responses in skeletal muscles induce an inflammatory response and adipogenesis in the BM and that the CXCL12-CXCR4 (C-X-C chemokine receptor 4) axis is important for T-cell homing to the BM. Antagonism of CXCR4 attenuated BM inflammation and increased bone mass in MKO mice. In humans, patients with low body mass index (BMI = 17.2 ± 0.42 kg/m2 ) harboured a larger population of proinflammatory and cytotoxic senescent T-cells in the BMI (P < 0.05) and showed reduced expression of OxPhos subunits in the vastus lateralis, compared with controls with a normal BMI (23.7 ± 0.88 kg/m2 ) (P < 0.01). CONCLUSIONS: Defects in muscle mitochondrial OxPhos promote BM inflammation in mice, leading to decreased bone mass. Muscle mitochondrial dysfunction is linked to BM inflammatory cytokine secretion via the CXCL12-CXCR4 signalling axis, which is critical for inducing low bone mass.

Mitoribosome insufficiency in ß cells is associated with type 2 diabetes-like islet failure.

Genetic variations in mitoribosomal subunits and mitochondrial transcription factors are related to type 2 diabetes. However, the role of islet mitoribosomes in the development of type 2 diabetes has not been determined. We investigated the effects of the mitoribosomal gene on ß-cell function and glucose homeostasis. Mitoribosomal gene expression was analyzed in datasets from the NCBI GEO website (GSE25724, GSE76894, and GSE76895) and the European Nucleotide Archive (ERP017126), which contain the transcriptomes of type 2 diabetic and nondiabetic organ donors. We found deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1. The phenotypes of haploinsufficiency in a single mitoribosomal gene were examined using ß-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1beta+/- mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased ß-cell mass associated with higher expression of Reg family genes. However, Crif1beta+/- mice showed earlier islet failure in response to high-fat feeding, which was exacerbated by aging. Haploinsufficiency of a single mitoribosomal gene predisposes rodents to glucose intolerance, which resembles the early stages of type 2 diabetes in humans.

Cellular and Intercellular Homeostasis in Adipose Tissue with Mitochondria-Specific Stress.

Paracrine interactions are imperative for the maintenance of adipose tissue intercellular homeostasis, and intracellular organelle dysfunction results in local and systemic alterations in metabolic homeostasis. It is currently accepted that mitochondrial proteotoxic stress activates the mitochondrial unfolded protein response (UPRmt) in vitro and in vivo. The induction of mitochondrial chaperones and proteases during the UPRmt is a key cell-autonomous mechanism of mitochondrial quality control. The UPRmt also affects systemic metabolism through the secretion of cell non-autonomous peptides and cytokines (hereafter, metabokines). Mitochondrial function in adipose tissue plays a pivotal role in whole-body metabolism and human diseases. Despite continuing interest in the role of the UPRmt and quality control pathways of mitochondria in energy metabolism, studies on the roles of the UPRmt and metabokines in white adipose tissue are relatively sparse. Here, we describe the role of the UPRmt in adipose tissue, including adipocytes and resident macrophages, and the interactive roles of cell non-autonomous metabokines, particularly growth differentiation factor 15, in local adipose cellular homeostasis and systemic energy metabolism.

Primary Cilia Mediate TSH-Regulated Thyroglobulin Endocytic Pathways.

Primary cilia are sensory organelles with a variety of receptors and channels on their membranes. Recently, primary cilia were proposed to be crucial sites for exocytosis and endocytosis of vesicles associated with endocytic control of various ciliary signaling pathways. Thyroglobulin (Tg) synthesis and Tg exocytosis/endocytosis are critical for the functions of thyroid follicular cells, where primary cilia are relatively well preserved. LRP2/megalin has been detected on the apical surface of absorptive epithelial cells, including thyrocytes. LRP2/megalin on thyrocytes serves as a Tg receptor and can mediate Tg endocytosis. In this study, we investigated the role of primary cilia in LRP2/megalin expression in thyroid gland stimulated with endogenous TSH using MMI-treated and Tg-Cre;Ift88flox/flox mice. LRP2/megalin expression in thyroid follicles was higher in MMI-treated mice than in untreated control mice. MMI-treated mice exhibited a significant increase in ciliogenesis in thyroid follicular cells relative to untreated controls. Furthermore, MMI-induced ciliogenesis accompanied increases in LRP2/megalin expression in thyroid follicular cells, in which LRP2/megalin was localized to the primary cilium. By contrast, in Tg-Cre;Ift88flox/flox mice, thyroid with defective primary cilia expressed markedly lower levels of LRP2/megalin. Serum Tg levels were elevated in MMI-treated mice and reduced in Tg-Cre;Ift88flox/flox mice. Taken together, these results indicate that defective ciliogenesis in murine thyroid follicular cells is associated with impaired LRP2/megalin expression and reduced serum Tg levels. Our results strongly suggest that primary cilia harbors LRP2/megalin, and are involved in TSH-mediated endocytosis of Tg in murine thyroid follicles.

Th2 Cytokines Increase the Expression of Fibroblast Growth Factor 21 in the Liver.

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13-STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.

Review of physiotherapy service for athletes of 2018 Olympic Winter games: Consideration of preparation for two polyclinics.

OBJECTIVE: This study will provide to better understand the needs for physiotherapy services during the 2018 PyeongChang Olympic Winter Games (POG) from two polyclinics. It is necessary to understand the needs and what physiotherapists do during the Olympic Winter games for first time. DESIGN: An observational study. SETTING: 2018 PyeongChang Olympic Winter Games. PARTICIPANTS: Athletes who visited the physiotherapy department of polyclinics. RESULTS: During 25 the days of the POG, a total of 125 athletes (n = 125, 83 males, 42 females) visited the two polyclinics. Of all visits, 69.6% were from the mountain polyclinic and 30.4% from the city. There were three reasons for visit, most of the reason for visit was injury and injury with recovery or injury prevention. Overall, the injury rate (per 1000 athletes) was 42.8 across 13 sports visited the physiotherapy department during the POG. Total numbers of treatments sessions were 823 provided and electrophysical modalities (36.2%) was the most utilized service in POG. And also there were significant differences in the physiotherapy services provided at the two polyclinics. CONCLUSION: As each polyclinic differed in location, they addressed different populations of athletes; hence, the study provides insights into the injury trends and different physiotherapy treatments.

Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response.

Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISRmt) in liver mediates metabolic adaptation through hepatic metabokines.

The Role of Growth Differentiation Factor 15 in Energy Metabolism.

Growth differentiation factor 15 (GDF15) is receiving great interest beyond its role as an aging and disease-related biomarker. Recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), suggests a central role in appetite regulation. However, there is also considerable evidence that GDF15 may have peripheral activity through an as-of-yet undiscovered mode of action. This raises the question as to whether increased GDF15 induction during pathophysiologic conditions also suppresses appetite. The present review will briefly introduce the discovery of GDF15 and describe the different contexts under which GDF15 is induced, focusing on its induction during mitochondrial dysfunction. We will further discuss the metabolic role of GDF15 under various pathophysiological conditions and conclude with possible therapeutic applications.

Loss of Primary Cilia Results in the Development of Cancer in the Murine Thyroid Gland.

Communications at the interface between the apical membrane of follicular cells and the follicular lumen are critical for the homeostasis of thyroid gland. Primary cilia at the apical membrane of thyroid follicular cells may sense follicular luminal environment and regulate follicular homeostasis, although their role in vivo remains to be determined. Here, mice devoid of primary cilia were generated by thyroid follicular epithelial cell-specific deletion of the gene encoding intraflagellar transport protein 88 (Ift88 ). Thyroid follicular cell-specific Ift88-deficient mice showed normal folliculogenesis and hormonogenesis; however, those older than 7 weeks showed irregularly dilated and destroyed follicles in the thyroid gland. With increasing age, follicular cells with malignant properties showing the characteristic nuclear features of human thyroid carcinomas formed papillary and solid proliferative nodules from degenerated thyroid follicles. Furthermore, malignant tumor cells manifested as tumor emboli in thyroid vessels. These findings suggest that loss-of-function of Ift88/primary cilia results in malignant transformation from degenerated thyroid follicles.

The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases

Mitochondria perform essential roles as crucial organelles for cellular and systemic energy homeostasis, and as signaling hubs, which coordinate nuclear transcriptional responses to the intra- and extra-cellular environment. Complex human diseases, including diabetes, obesity, fatty liver disease and aging-related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OxPhos) function. However, a recent series of studies in animal models have revealed that an integrated response to tolerable mitochondrial stress appears to render cells less susceptible to subsequent aging processes and metabolic stresses, which is a key feature of mitohormesis. The mitochondrial unfolded protein response (UPRmt) is a central part of the mitohormetic response and is a retrograde signaling pathway, which utilizes the mitochondria-to-nucleus communication network. Our understanding of the UPRmt has contributed to elucidating the role of mitochondria in metabolic adaptation and lifespan regulation. In this review, we discuss and integrate recent data from the literature on the present status of mitochondrial OxPhos function in the development of metabolic diseases, relying on evidence from human and other animal studies, which points to alterations in mitochondrial function as a key factor in the regulation of metabolic diseases and conclude with a discussion on the specific roles of UPRmt and mitohormesis as a novel therapeutic strategy for the treatment of obesity and insulin resistance.

Reduced oxidative capacity in macrophages results in systemic insulin resistance.

Oxidative functions of adipose tissue macrophages control the polarization of M1-like and M2-like phenotypes, but whether reduced macrophage oxidative function causes systemic insulin resistance in vivo is not clear. Here, we show that mice with reduced mitochondrial oxidative phosphorylation (OxPhos) due to myeloid-specific deletion of CR6-interacting factor 1 (Crif1), an essential mitoribosomal factor involved in biogenesis of OxPhos subunits, have M1-like polarization of macrophages and systemic insulin resistance with adipose inflammation. Macrophage GDF15 expression is reduced in mice with impaired oxidative function, but induced upon stimulation with rosiglitazone and IL-4. GDF15 upregulates the oxidative function of macrophages, leading to M2-like polarization, and reverses insulin resistance in ob/ob mice and HFD-fed mice with myeloid-specific deletion of Crif1. Thus, reduced macrophage oxidative function controls systemic insulin resistance and adipose inflammation, which can be reversed with GDF15 and leads to improved oxidative function of macrophages.