The skeletal muscle plays a key role in thermogenesis and energy homeostasis in endotherms. Therefore, reduced skeletal muscle mass and function are closely associated with health disorders such as obesity and hypothermia. In humans, inactivity and nutritional deficiencies can lead to skeletal muscle atrophy. However, hibernating mammals, which can greatly suppress their metabolic rate, can maintain significant skeletal muscle mass even during prolonged periods of inactivity and nutritional restriction. This review focuses on how skeletal muscle contributes to maintaining body temperature as the organ that consumes the most energy, while also contributing to whole-organism homeostasis through its high metabolic flexibility in a self-sacrificing manner. Particularly, we reconceptualized muscle atrophy associated with the thermoregulatory process in terms of inter-organ metabolic interaction, proposing that sarcopenia is an integral component of systemic energy metabolism regulation. By deepening our understanding of the functional metabolic flexibility of skeletal muscle and its regulatory mechanisms, we can redefine sarcopenia as an adaptive response that contributes to maintaining metabolic homeostasis. This perspective could provide new insights into the pathophysiology of sarcopenia and metabolic disorders, and inform the development of more effective prevention and treatment strategies.

Males and females show significant differences in body structure, typical behavior, average life expectancy, and disease susceptibility. This review article introduces the current understanding and recent findings on the factors that lead to sexual dimorphism. First, recent studies have shown that sex chromosomes underlie male- and female-specific phenotypes through various mechanisms. For example, X chromosome inactivation exerts both positive and negative effects on female health, independent of sex hormone actions. Furthermore, differences in the frequency and clinical consequences of the mosaic loss of X and Y chromosomes have been implicated in sex differences in disease susceptibility and average life expectancy. In addition, sex-specific epigenetic regulation of the pseudoautosomal gene SHOX has been linked to the relative short stature of females. Second, an alternative steroidogenic pathway and novel non-aromatizable androgens have been specified in humans. These factors, together with classical sex hormones, likely contribute to the phenotypic differences between males and females. Elucidating the molecular basis of sexual dimorphism helps us understand the factors involved in human diversity.

A high body mass index (BMI) is associated with the onset of diabetes mellitus (DM). However, evidence regarding the association between changes in BMI and DM onset is limited, and the effect of annual BMI (kg/m²/year) change on DM onset is unknown. Therefore, we assessed the effects of changes in BMI and annual BMI on DM onset. We enrolled 13,949 participants aged 21–81 years who underwent an annual health checkup at least twice between April 2003 and March 2021 and examined the effect of BMI change and annual BMI change on DM onset. In total, 462 individuals newly developed DM. Compared with a BMI change of –0.25–<0.25, univariate and multivariate analyses—adjusted for age, sex, BMI, systolic blood pressure, creatinine, total cholesterol, triglycerides, alanine aminotransferase, hemoglobin A1c, and family history of DM—showed that a BMI change <–2 was associated with a lower risk, while 2 ≤ BMI change < 4 and 4 ≤ BMI change were associated with a higher risk of DM onset. In contrast, compared with –0.05 ≤ BMI change per year < 0.05, univariate and multivariate analyses showed a significant association between DM onset and 0.3 ≤ BMI change per year. In the age-stratified analysis, these associations were significant among younger and middle-aged participants but not in older adults. In conclusion, changes in BMI affect DM onset. Therefore, clinicians can prevent DM onset by providing guidance based on BMI and focusing on a ≥2 increase in BMI and a ≥0.3 increase per year of BMI in young and middle-aged individuals.

This study examined the association of physical activity (PA) and sedentary time (ST) with the risk of non-alcoholic fatty liver disease (NAFLD) in adults with and without diabetes mellitus (DM). The study used data from the 2017–2020 National Health and Nutrition Examination Survey and conducted weighted logistic regression analysis to examine the association between PA, ST and NAFLD risk in individuals with and without DM. A total of 4,805 participants were included, with a weighted prevalence of NAFLD of 36% and a weighted prevalence of DM of 13.3%. Participants were divided into quartiles (Q1–Q4) based on PA levels (MET-min/week) and ST (min/day), with Q1 representing the lowest activity/shortest sitting time. In the total population, for PA, the risk of NAFLD in the Q2 and Q3 groups was reduced by 0.593 and 0.660 times, respectively, compared with the Q1 group. For ST, relative to the Q1 group, the NAFLD risk increased in the Q2, Q3 and Q4 groups by 1.420, 1.361 and 1.690 times, respectively. The dose–response analysis revealed that in the total population, NAFLD risk decreased when PA levels were between 1,553.4 and 30,402.3 metabolic equivalent of task (MET)-min/week (p_non-linear = 0.016). Among individuals without DM, for PA, the NAFLD risk in the Q2 and Q3 groups was 0.571 and 0.648 times lower, respectively, than that in the Q1 group. When PA was within the range of 1,775.3 to 24,410.6 MET-min/week, the risk of NAFLD was reduced (p_non-linear = 0.033). Patterns of association between PA, ST, and NAFLD appeared to differ between individuals with and without DM; however, multiplicative interaction terms were not statistically significant.

Diabetes mellitus (DM) is a key global public health issue with rising incidence. The triglyceride-glucose (TyG) index has been widely applied to assess insulin resistance and metabolic abnormalities in recent years. However, the relation of the TyG index with DM is elusive when combined with central obesity indicators. This research was conducted to probe into the relationship between TyG-derived indices and DM. A total of 10,729 participants from the NHANES database were enrolled, of whom 1,984 had DM. The linkage of five TyG-derived indices with DM was examined using a weighted logistic regression model. At the same time, stratified analysis was undertaken on different gender and age subgroups. To evaluate the predictive performance of each indicator, ROC curve analysis was undertaken to examine the predictive capability of different indicators. The findings indicated that all TyG-derived indices were greatly positively linked with the risk of DM. The AUC values of TyG-CI and TyG-WWI were considerably higher than those of the TyG index and other indicators, demonstrating a stronger capability to predict the risk of DM. In subgroup analyses, both TyG-CI and TyG-WWI exhibited high robustness across different populations regardless of gender or age. The indices with the TyG index combined with indicators related to central obesity, especially TyG-CI and TyG-WWI, are effective tools for predicting the risk of DM.

β3-Adrenoceptors (β3ARs) are expressed in the adipose tissue, the brain, and the bladder. In rodents, selective β3AR agonists have been shown to reduce normal chow intake through central and peripheral mechanisms. However, the impact of β3AR agonists on nutritional balance, as well as the relative contribution of each organ system to this effect, remains elusive. In this study, we aimed to determine whether the peripheral effect of β3AR agonists on food intake is nutrient-specific or energy in general using food choice experiments that allow for independent analysis of energy and nutrients. Mice were presented with two different diet options (normal diet [ND] vs. high-sucrose diet [HSD], high-fat diet [HFD], or high-protein diet [HPD]), and the effects of the β3AR agonist CL316,243 on the intake of these diets were examined. Treatment with CL316,243 reduced total energy intake, primarily through decreased consumption of HSD, HFD, and HPD. Accordingly, CL316,243 reduced food intake in a non-nutrient-specific manner, resulting in decreased caloric intake. In addition, CL316,243 increased plasma levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). In the ND vs. HSD food choice test, CL316,243 reduced HSD intake, even in liver-specific Fgf21 knockout mice. Furthermore, CL316,243 reduced food intake in mice with diet-induced obesity. These findings suggest that the CL316,243-mediated reduction in HSD intake occurs independently of liver-derived FGF21. Moreover, elevated plasma GDF15 levels were positively associated with reduced food intake induced by CL316,243.

Reports on long-term safety and effectiveness of daily GH replacement therapy in Japanese children with short stature due to Noonan syndrome (NS) are limited. This post-marketing, prospective, non-interventional study (ClinicalTrials.gov NCT03435627) evaluated the long‑term safety and effectiveness of daily GH therapy in this patient population. The study took place at 22 sites in Japan during November 2017–January 2022. Seventy participants were enrolled and received Norditropin^® at least once during the study as per routine clinical practice: new patients (n = 35) received Norditropin^® (somatropin) after study initiation and existing patients (n = 35) were previously enrolled in a 4-year trial of Norditropin^® for NS (ClinicalTrials.gov NCT01927861). The main outcome measures were adverse drug reactions (ADRs) and serious adverse events (SAEs). Improvements in height were also measured. In total, four new patients experienced five ADRs and one new patient experienced one SAE. Five existing patients experienced one ADR each and three existing patients experienced one SAE each. One existing patient with pre-existing cardiomyopathy who experienced an SAE (arrhythmia) died during the study; Norditropin^® causality was judged ‘unlikely.’ Change from baseline in mean (SD) height standard deviation score (SDS), according to Japanese and NS standards, was 1.01 (0.5) and 0.92 (0.3) for new patients and 1.01 (1.0) and 1.31 (0.8) for existing patients, respectively. Our results show that Norditropin^® effectively improved height outcomes in Japanese children with NS and was well tolerated with no new safety issues identified. For patients with NS and cardiomyopathy receiving GH therapy, careful monitoring is advised.

Vitamin D (VD) insufficiency in pregnant women is a serious health problem worldwide. To prevent VD insufficiency during pregnancy, several guidelines recommend 600 IU/day VD for all pregnant women. In Japan, no national guidelines for preventing VD insufficiency have been implemented, and no study has evaluated adequate VD intake in pregnant women; however, the number of pregnant women taking commercial dietary supplements containing VD has increased in recent years. This study aimed to examine the effects of maternal commercial supplementation of VD on 25-hydroxyvitamin D (25(OH)D) levels in newborns. We retrospectively analyzed the serum 25(OH)D levels in 279 four-days-old newborns born at the Saitama City Hospital from 2022 to 2023. Newborns were classified into a supplement group (mothers who took VD-containing commercial supplements regularly throughout pregnancy; n = 103) and a non-supplement group (mothers who did not take any supplements during pregnancy; n = 176). The study findings revealed that serum 25(OH)D levels in newborns in the supplement group were higher than those in the non-supplement group (median [interquartile range]: supplement group 17.2 [14.6, 22.9] vs. non-supplement group 14.3 [11.6, 16.7], p < 0.001). In the supplement group, approximately 70% of newborns still showed VD insufficiency. Although the maternal use of VD-containing commercial supplements during pregnancy increased the serum 25(OH)D levels in newborns at four days of age, additional measures, such as VD supplementation for newborns, are needed to improve neonatal VD status.

Children born small for gestational age (SGA) who fail to experience catch-up growth often remain short-statured with heterogeneous etiologies, including genetic factors. This study aimed to investigate Insulin-like Growth Factor 1 Receptor (IGF1R) gene alterations and their clinical relevance in 66 Korean children born SGA with persistent short stature. All the subjects underwent detailed phenotyping and molecular analyses. Two patients carried heterozygous deletions encompassing the entire IGF1R gene, as confirmed by chromosomal microarray analysis. Both patients exhibited advanced bone age, with one showing a favorable response to growth hormone therapy. Additionally, 14 variants of uncertain significance were identified, with one rare missense variant (c.158C>T, p.Thr53Met) showing a high predicted pathogenicity. Subgroup analysis showed that severe SGA was associated with lower mid-parental height, and those with an insulin-like growth factor 1 standard deviation score of ≥0 had less bone age delay, but no clear auxological differences were observed between subgroups. These patterns, although not definitive, may help to identify SGA-short children who warrant further evaluation for IGF1R-related growth impairment. Exploratory clustering revealed two subgroups but failed to show distinct phenotypic separation. Although no strong genotype–phenotype correlations were observed, this study highlights the potential clinical value of identifying IGF1R deletions and suggests that molecular and phenotypic profiling may offer hypothesis-generating insights into SGA-related growth disorders. Our findings underscore the importance of integrating genetic screening into the diagnostic workup for children born SGA with unexplained growth failure, and the need for future studies to functionally characterize rare IGF1R variants.

A meta-analysis of cohort studies found a positive association between white rice consumption and chronic disease risk, particularly in women. However, the association between rice intake and obesity remains inconsistent across populations. We aimed to examine the relationship between rice intake and obesity stratified by sex and age. This cross-sectional study used nationwide registry data from Japanese type 2 diabetes outpatients (2014–2019). Obesity was defined as BMI ≥25 kg/m². The study included 1,565 outpatients aged 30–89 years (mean age: 62.3 ± 11.6 years), with 63.1% being male. Rice intake was associated with a diet low in energy from protein, fiber density, and dairy products. In adjusted multivariate analysis, older women in the highest tertile of rice intake had a higher prevalence of obesity (95% CI = 1.104–4.260, p trend = 0.042); however, this association lost significance after adjusting for fiber density (95% CI = 0.864–3.558, p trend = 0.080). In younger women, an inverse association with obesity emerged after fiber density adjustment in the supplementary quartile analysis. No significant associations were found in men. These results suggest that the association between rice intake and obesity is influenced by overall dietary quality rather than rice consumption alone. Promoting greater dietary diversity while maintaining traditional staples like rice may be a practical strategy to improve diet quality in Japan. Prospective studies in Japanese and other populations are needed to confirm these associations.

PaTHway Japan is an ongoing, phase 3, multicenter, single-arm, open-label trial comprised of a 26-week efficacy period with an extension period through week 182 designed to demonstrate the efficacy, safety, and tolerability of palopegteriparatide in Japanese individuals with hypoparathyroidism. Japanese men and women (≥18 years of age) with hypoparathyroidism of any etiology (≥26 weeks) taking stable doses of active vitamin D were enrolled across five sites in Japan. Once-daily palopegteriparatide was self-administered subcutaneously via a pre-filled pen injector. Titration of palopegteriparatide and conventional therapy was performed according to a protocol-specified algorithm. The main outcomes measures included the proportion of participants at week 26 who achieved albumin-adjusted serum calcium in the normal reference range, independence from active vitamin D, and independence from therapeutic doses of elemental calcium. Thirteen participants were enrolled. Hypoparathyroidism etiology was most commonly idiopathic, followed by postsurgical and genetic causes. After 26 weeks of treatment with palopegteriparatide, 92% (12/13) of participants achieved the primary multi-component endpoint. Of the participants who entered the extension period, 92% (11/12) met the multi-component endpoint at week 52. Adverse events were mild to moderate in severity; none led to discontinuation of palopegteriparatide treatment. These findings in Japanese adults are consistent with results of the pivotal phase 3 and phase 2 North American/European trials and demonstrate the reproducibility of the palopegteriparatide treatment benefit in diverse populations and geographies. Japan Registry of Clinical Trials ID: jRCT2051210058.

Differences of sex development (DSD) are congenital conditions in which chromosomal, gonadal, and anatomical sex characteristics are discordant with typical male or female development. These clinical practice guidelines provide evidence-based recommendations for the diagnosis and management of individuals with DSD across the lifespan. The guidelines were developed by a multidisciplinary committee of specialists representing pediatric endocrinology, adult endocrinology, urology, gynecology, psychiatry, and psychology. The committee employed a systematic review of the literature and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to assess the strength of recommendations and the quality of evidence. Key areas addressed include the initial management of infants with atypical genitalia, diagnostic approaches, hormonal treatment, surgical interventions, gonadal tumor risk assessment, fertility preservation, and the transition from pediatric to adult care. The guidelines integrate international best practices with Japan’s unique sociocultural, healthcare, and legal contexts for optimal DSD management and aim to improve clinical care for individuals with DSD while acknowledging the limited high-quality evidence in many aspects of DSD management.

Acquired hypothalamic obesity (aHO) presents as rapid, clinically relevant, and persistent weight gain due to hypothalamic damage, and leads to significant morbidity/mortality and decreased quality of life. Causes include craniopharyngioma and other space-occupying lesions, neurosurgical intervention, irradiation, and traumatic brain injury. This review summarizes the evidence and provides expert opinion on diagnostic criteria for aHO. Eight experts in neuroendocrinology and neurosurgery from Japan and Europe participated in a multidisciplinary meeting at the 57^th Annual Meeting of the Japanese Society for Pediatric Endocrinology, Yokohama, Japan, 2024. Thereafter, three experts from Korea joined the discussion. Data were sourced from a search of the databases Web of Science, MEDLINE/PubMed, and Embase for reports published since 2000. Expert opinion of the authors was used substantially when no published data were available. The consensus on diagnostic criteria for aHO included: a.) traumatic event or (oncological) disease leading to hypothalamic lesions/damage detectable on magnetic resonance imaging (MRI); b.) rapid (occurring during the first 12 months after surgery/diagnosis), persisting (for 24 months after surgery), and clinically significant increase in body mass index (BMI) (≥5% BMI increase in adult; ≥1.0 standard deviation score (SDS) BMI increase in pediatric patients) starting during the first 12 months following the onset of hypothalamic damage under clinical and anthropometric monitoring at 3 months intervals; c.) obesity of a certain level (BMI SDS ≥+2.0 standard deviations (SD) in pediatric; BMI ≥25 kg/m² or BMI ≥30 kg/m² in adult patients), depending on racial and ethnic characteristics.

Cushing’s disease (CD) is a rare but serious endocrine disorder caused by excessive cortisol secretion due to adrenocorticotropic hormone–secreting pituitary tumors. Despite recent developments in diagnostic criteria and treatment options, CD remains associated with substantial comorbidities and mortality. Early and accurate diagnosis is thus essential. Both the Korean Endocrine Society (KES) and Japan Endocrine Society (JES) guidelines are intended to standardize diagnostic approaches to CD, and they share common principles; however, notable differences exist, particularly in biochemical testing thresholds and imaging recommendations. This consensus statement integrates clinical evidence and expert practice from both the KES and JES to establish harmonized recommendations for biochemical evaluation, imaging, and differential testing. This unified framework is intended to enhance diagnostic precision and improve clinical outcomes across East Asian populations.