Hisakazu Nakajima

Hematopoietic Contribution to Skeletal Muscle Regeneration in Acid α-Glucosidase Knockout Mice

Recent studies have shown that cells from bone marrow (BM) can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved remain unknown. We performed BM transplantation in acid α-glucosidase (GAA) knockout mice, a model of glycogen storage disease type II, and our observations suggested that the BM cells contribute to skeletal muscle fiber formation. Furthermore, we showed that most CD45+:Sca1+ cells have a donor character in regenerating muscle of recipient mice. Based on these findings, CD45+:Sca1+ cells were sorted from regenerating muscles. The cell number was increased with granulocyte colony-stimulating factor after cardiotoxin injury, and the cells were transplanted directly into the tibialis anterior (TA) muscles of GAA knockout mice. Sections of the TA muscles stained with anti-laminin-α2 antibody showed that the number of CD45+:Sca1+ cells contributing to muscle fiber formation and glycogen levels were decreased in transplanted muscles. Our results indicated that hematopoietic stem cells, such as CD45+:Sca1+ cells, are involved in skeletal muscle regeneration.

The Relationship in Japanese Infants between a Genetic Polymorphism in the Promoter Region of the Insulin-Like Growth Factor I Gene and the Plasma Level

Background: Evidence is accumulating that the promoter region of the insulin-like growth factor I (IGF-I) gene polymorphism and low levels of IGF-I are associated with type 2 diabetes, cardiovascular disease and birth weight; however, the number of wild-type alleles is different in each country. Objectives: This study aimed to examine the 737/738 marker, a cytosine–adenine repeat in the promoter region of the IGF-I gene polymorphism, and plasma IGF-I levels in Japanese infants and analyze the genetic background. Methods: Data were collected for 15 months in Kyoto Prefectural University of Medicine. The body composition parameters of all infants were determined at birth. At 5 days after birth, we took blood samples to measure the product size of the promoter region of the IGF-I gene polymorphism and plasma IGF-I. Results: In a population-based sample of 160 subjects, 6 different alleles and 16 genotypes were identified in the promoter region of the IGF-I gene polymorphism. The existence of a 196-bp allele has proved to result in a low plasma IGF-I level, a small head and chest circumference (p < 0.05) and no significant for premature birth, short-birth height and low-birth weight. Conclusions: This is the first study showing the role of the promoter region of the IGF-I gene polymorphism and the level of plasma IGF-I and body composition parameters in Japanese infants. Our results suggest genetical influence on prenatal growth and serum IGF-I levels.

Relapsing 6q24-related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase-4 inhibitor: a case report

The most common form of transient neonatal diabetes mellitus (TNDM) is 6q24‐related TNDM. Patients are treated with insulin during the neonatal period until spontaneous remission. However, diabetes often recurs in adolescence, and there is no standard therapy for patients with a relapse. A paternal duplication at the 6q24 critical region spanning the pleiomorphic adenoma gene‐like 1 PLAGL1 gene was found in a Japanese patient with TNDM relapse. The patient was treated with a dipeptidyl peptidase‐4 (DPP4) inhibitor, alogliptin, at a dose of 25 mg per day. Immediately after treatment initiation, his hemoglobin A1c (HbA1c) levels dropped from 7.0–7.5% (52–58 mmol/mol) to 6.0–6.5% (41–47 mmol/mol) and remained stable for over a year. We reported the successful treatment of relapsed 6q24‐related TNDM with a DPP4 inhibitor. Although insulin has been the conventional treatment for such patients, treatments targeting the GLP1 pathway can be a useful alternative because these patients retain the β cell mass and responsiveness through G protein‐coupled pathways.

De novo IGF2 mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly

Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole‐exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver–Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation‐ and methylation‐sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.

Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice

Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO’s anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO’s suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT’s endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO’s improvement of obesity and glucose homeostasis can be attributed to increased iBAT thermogenic capacity and activation of BAT’s endocrine functions.

Review: Miglitol has potential as a therapeutic drug against obesity

The number of obese patients has increased annually worldwide. Therefore, there is a strong need to develop a new effective and safe anti-obesity drug. Miglitol is an alpha-glucosidase inhibitor (αGI) that is commonly used as an anti-diabetic drug, and there is growing evidence that it also has anti-obesity effects. Miglitol has been shown to reduce body weight and ameliorate insulin resistance in both clinical trials with adult patients and in rodent models of obesity. Although the specific mechanism of action of this effect remains unclear, some mechanisms have been suggested through experimental results. Miglitol has been shown to inhibit adipogenesis of white adipocytes in vitro, activate brown adipose tissue (BAT) in mice, influence bile acid metabolism in mice, and regulate the secretion of incretin hormones in humans. Among these results, we consider that BAT activation is likely the definitive mediator of miglitol’s anti-obesity effect. A unique advantage of miglitol is that it is already used as an anti-diabetic drug with no severe side effects, whereas many of the anti-obesity drugs developed to date have been withdrawn because of their severe side effects. Miglitol is currently used clinically in a limited number of countries. In this review, we provide an overview of the state of research on miglitol for obesity treatment, emphasizing that it warrants more detailed attention. Overall, we demonstrate that miglitol shows good potential as a therapeutic for the treatment of obesity. Thus, we believe that further investigations of how it exerts its anti-obesity effect will likely contribute to the development of a new class of safe and effective drugs against obesity.

Traumatic herniation of the buccal fat pad.

Traumatic herniation of the buccal fat pad is a rare traumatic disease. Treatment consists of either excision or replacement. We herein report the first case in which a traumatic herniation of the buccal fat pad healed naturally. It was necessary to differentiate the disease from lipoblastoma. A 17‐month‐old boy was admitted to a clinic with an intraoral tumor that had suddenly increased in size. The tumor was diagnosed as herniation of the buccal fat pad on pathology of a biopsy specimen. In the present case, the escaped buccal fat body returned naturally and engrafted without dysfunction or facial defects. Given that young children may easily fall down with various objects in their mouth, care is required to prevent traumatic accidents. Traumatic herniation of the buccal fat pad should be considered in the differentiation of tumors of the oral cavity in young children.

Angiotensin 1–7 stimulates brown adipose tissue and reduces diet-induced obesity

The renin-angiotensin system is a key regulator of metabolism with beneficial effects of the angiotensin 1-7 (Ang 1-7) peptide. We hypothesized that the antiobesity effect of Ang 1-7 was related to the stimulation of brown adipose tissue (BAT). We administered Ang 1-7 (0.54 mg kg-1 day-1) for 28 days via implanted micro-osmotic pumps to mice with high-fat diet (HFD)-induced obesity. Ang 1-7 treatment reduced body weight, upregulated thermogenesis, and ameliorated impaired glucose homeostasis without affecting food consumption. Furthermore, Ang 1-7 treatment enlarged BAT and the increased expression of UCP1, PRDM16, and prohibitin. Alterations in PRDM16 expression correlated with increased AMPK and phosphorylation of mTOR. Ang 1-7 treatment elevated thermogenesis in subcutaneous white adipose tissue without altering UCP1 expression. These changes occurred in the context of decreased lipid accumulation in BAT from HFD-fed mice, preserved insulin signaling concomitant with phosphorylation of hormone-sensitive lipase and decreased expression of perilipin. These data suggest that Ang 1-7 induces brown adipocyte differentiation leading to upregulation of thermogenesis and improved metabolic profile in diet-induced obesity. Enhancing Ang 1-7 action represents a promising therapy to increase BAT and to reduce the metabolic complications associated with diet-induced obesity.

Arterial stiffness in junior high school students: Longitudinal observations

Early atherosclerotic change is found even in childhood, and there is an urgent need to clarify the factors causing childhood atherosclerosis and take preventive measures. Early detection of the contributing risk factors is crucial to facilitate preventive measures. Pulse wave velocity (PWV) is a widely used technique for the assessment of atherosclerosis in children.

Decrement in bone mineral density after parathyroidectomy in a pediatric patient with primary hyperparathyroidism

Abstract. Primary hyperparathyroidism (PHT) causes increased bone turnover, leading to reduction in bone mineral density (BMD). Parathyroidectomy is a definitive therapy and improves BMD in adult patients with PHT. However, there are no reports regarding alterations of BMD in pediatric or adolescent patients with PHT. Here, we report a case of a 13-yr-old boy with PHT who was referred to our institution for evaluation of hypercalcemia and hyperparathyroidism. Radiological investigation revealed an ectopic parathyroid adenoma below the right thyroid lobe. A minimally invasive radio-guided parathyroidectomy was successfully performed. We followed up the patient’s BMD for three years both before and after parathyroidectomy. Over the course of three years, his BMD was steadily decreased, with z-scores of +0.506 at 13 yr and 9 mo, +0.162 at 14 yr and 9 mo, and –0.411 at 15 yr and 9 mo. BMD usually increases during peak height velocity in an adolescent and improves after parathyroidectomy in adult patients with PHT. However, our patient showed decreased BMD z-scores following parathyroidectomy. Therefore, the patient had an increased risk of fracture after parathyroidectomy and was followed up closely. Both height and BMD should be carefully evaluated after parathyroidectomy in pediatric and adolescent patients with PHT.