Meal-related oscillations in the serum serotonin levels in healthy young men.

CONTEXT: Serotonin acts as a neurotransmitter in the central and enteric nervous systems, modulating psychological, metabolic and gastrointestinal functions. Serotonin is also found in the serum or plasma, indicating its potential role as a hormone. OBJECTIVE: We aimed to assess the 24-hour diurnal profile of serum serotonin in relation to meal ingestion in healthy adult men. METHODS: Ten healthy (5 lean and 5 obese) male subjects were enrolled in this study. Blood samples were drawn every 30-60 minutes throughout a 24-hour period to determine the serotonin levels. Three meals were provided on a fixed schedule. To confirm the effect of meal intake on serum serotonin levels, 4 subjects underwent fasting until 1500 h and were then provided a meal without notice. RESULTS: Serum serotonin levels had distinct diurnal variations, with the highest levels early in the morning and the lowest levels in the midafternoon and during sleep. Notably, these diurnal oscillations were markedly reduced in obese subjects. Fluctuations in serum serotonin levels were associated with meal intake, and the levels peaked 30 minutes before meals and exhibited a trough during the postprandial period. Fasting blunted the meal-related oscillations in serum serotonin levels. Moreover, unexpected meal intake did not lead to a premeal increase in serum serotonin levels. CONCLUSIONS: Serum serotonin levels displayed meal-related diurnal oscillations, which were disrupted by fasting and obesity. These findings suggest the possibility that circulating serotonin modulates metabolic function in humans.

Angiopoietin-like peptide 4 regulates insulin secretion and islet morphology.

Insulin secretion from pancreatic islet ß-cells is primarily regulated by the blood glucose level, and also modulated by a number of biological factors produced inside the islets or released from remote organs. Previous studies have shown that angiopoietin-like protein 4 (Angptl4) controls glucose and lipid metabolism through its actions in the liver, adipose tissue, and skeletal muscles. In this present study, we investigated the possible role of Angptl4 in the regulation of insulin secretion from pancreatic islets. Angptl4 was found to be highly expressed in the α-cells but not ß-cells of rodent islets. Moreover, treatment of rodent islets with Angptl4 peptide potentiated glucose-stimulated insulin secretion through a protein kinase A-dependent mechanism. Consistently, Angptl4 knockout mice showed impaired glucose tolerance. In the cultured islets from Angptl4 knockout mice, glucose-stimulated insulin secretion was significantly lower than in islets from wild type mice. Angptl4 peptide replacement partially reversed this reduction. Moreover, Angptl4 knockout mice had dysmorphic islets with abnormally distributed α-cells. In contrast, the ß-cell mass and distribution were not significantly altered in these knockout mice. Our current data collectively suggest that Angptl4 may play a critical role in the regulation of insulin secretion and islet morphogenesis.

Leptin signalling pathways in hypothalamic neurons.

Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways.

Preclinical comparison study of experimental peri-implantitis between alveolar ridge preservation and spontaneous healing sites in infected and noninfected tooth: a randomized blinded in vivo study.

BACKGROUND: This study compared the progression of experimental peri-implantitis between alveolar ridge preservation (ARP) and spontaneous healing (SH) sites in infected (IT) and noninfected tooth (NIT). METHODS: Bilateral mandibular third or fourth premolars of six beagle dogs were randomly assigned to IT and NIT groups. Before extraction, chronic dehiscence defects were created at the mesial root of mid-buccal area in IT group. Four weeks later, the mesial roots of the third and fourth premolars were extracted in all groups.ARP procedure was randomly conducted on one side of the extraction sockets using collagenated bovine bone substitutes and resorbable collagen membrane, and contralateral side was allowded spontaneous healing. After 12 weeks of healing, bone-level implants (ϕ 3.6 × 8.0 mm) were placed at the extraction sockets. Three months of ligature induced peri-implantitis and three months of spontaneous progression were allowed, with radiographs taken at each phase. Biopsies were retrieved at the implant site for histomorphometric, immunohistochemical, and polarized light-microscopic analyses. RESULTS: Radiography demonstrated that the changes in the marginal bone level during the spontaneous progression period showed no significant differences between ARP and SH sites. Only small and/or nonsignificant differences in the progression of peri-implantitis were observed between ARP and SH sites in histomorphometric, immunohistochemical, and polarized light microscopic analyses. Additionally, the IT and NIT groups exhibited similar outcomes for most parameters. CONCLUSION: ARP with xenogenic bone substitutes might provide similarly robust results as SH sites regarding the progression of experimental peri-implantitis, irrespective of the infected or noninfected nature of the site before tooth extraction.

Stomach clusterin as a gut-derived feeding regulator.

The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and cholecystokinin, can act through the vagus nerve. We previously reported the satiety effect of hypothalamic clusterin, but the impact of peripheral clusterin remains unknown. In this study, we administered clusterin intraperitoneally to mice and observed its ability to suppress fasting-driven food intake. Interestingly, we found its synergism with cholecystokinin and antagonism with ghrelin. These effects were accompanied by increased c-fos immunoreactivity in nucleus tractus solitarius, area postrema, and hypothalamic paraventricular nucleus. Notably, truncal vagotomy abolished this response. The stomach expressed clusterin at high levels among the organs, and gastric clusterin was detected in specific enteroendocrine cells and the submucosal plexus. Gastric clusterin expression decreased after fasting but recovered after 2 hours of refeeding. Furthermore, we confirmed that stomachspecific overexpression of clusterin reduced food intake after overnight fasting. These results suggest that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis. [BMB Reports 2024; 57(3): 149-154].

Nationwide survey of acromegaly in South Korea.

CONTEXT: It was previously reported in Korea that there were 1.4 case per million per year of acromegaly. This was low in comparison with the extrapolated values of Western European countries. We expected that the incidence of acromegaly would be much higher now because of recently improved medical facilities, diagnostic tools and coverage of medical insurance to all the population of South Korea. OBJECTIVE: The purpose of this nationwide survey was to examine the incidence and prevalence of patients with acromegaly, mode of treatment and outcome of surgical treatment of recent 5 years. DESIGN AND PATIENTS: We requested and collected the medical records of all possible patients with acromegaly from 74 secondary or tertiary medical institutes in Korea from 2003 to 2007 retrospectively. MEASUREMENTS: Date of diagnosis and treatment, tumour size, pre- and postoperative hormonal level, treatment modality and usage of medication were collected. RESULTS: During 5 years, 1350 patients with acromegaly had been registered. The average annual incidence was 3.9 cases per million during this period, and prevalence had increased up to 27.9 cases per million in 2007. Male/female ratio was 1:1.2, and mean age at diagnosis was 44.1 years. Macroadenoma was dominant (82.9%). Transsphenoidal adenoidectomy was used the most as primary treatment (90.4%). CONCLUSIONS: This Korean acromegaly survey offers a realistic overview of the predominant epidemiological characteristics of acromegaly in Korea. Annual incidence was at a similar level with western countries. Efforts to diagnose and control the disease earlier are recommended.

Enhanced neuronal activity by suffruticosol A extracted from Paeonia lactiflora via partly BDNF signaling in scopolamine-induced memory-impaired mice.

Neurodegenerative diseases are explained by progressive defects of cognitive function and memory. These defects of cognition and memory dysfunction can be induced by the loss of brain-derived neurotrophic factors (BDNF) signaling. Paeonia lactiflora is a traditionally used medicinal herb in Asian countries and some beneficial effects have been reported, including anti-oxidative, anti-inflammatory, anti-cancer activity, and potential neuroprotective effects recently. In this study, we found that suffruticosol A is a major compound in seeds of Paeonia lactiflora. When treated in a SH-SY5 cell line for measuring cell viability and cell survival, suffruticosol A increased cell viability (at 20 µM) and recovered scopolamine-induced neurodegenerative characteristics in the cells. To further confirm its neural amelioration effects in the animals, suffruticosol A (4 or 15 ng, twice a week) was administered into the third ventricle beside the brain of C57BL/6 mice for one month then the scopolamine was intraperitoneally injected into these mice to induce impairments of cognition and memory before conducting behavioral experiments. Central administration of suffruticosol A into the brain restored the memory and cognition behaviors in mice that received the scopolamine. Consistently, the central treatments of suffruticosol A showed rescued cholinergic deficits and BDNF signaling in the hippocampus of mice. Finally, we measured the long-term potentiation (LTP) in the hippocampal CA3-CA1 synapse to figure out the restoration of the synaptic mechanism of learning and memory. Bath application of suffruticosol A (40 µM) improved LTP impairment induced by scopolamine in hippocampal slices. In conclusion, the central administration of suffruticosol A ameliorated neuronal effects partly through elevated BDNF signaling.

Temporal Trends of the Prevalence of Abdominal Obesity and Metabolic Syndrome in Korean Children and Adolescents between 2007 and 2020.

Background: The prevalence of obesity in children and adolescents is increasing worldwide, which is of concern because obesity can lead to various complications such as metabolic syndrome (MS). Waist circumference (WC) and waist-height ratio (WHtR) are useful indicators of abdominal obesity and MS. In this study, we investigate trends in the prevalence of abdominal obesity and MS using two different references. Methods: Data from the Korea National Health and Nutrition Examination Survey (2007 to 2020) were used. In total, 21,652 participants aged 2 to 18 years and 9,592 participants aged 10 to 18 years were analyzed for abdominal obesity and MS, respectively. The prevalence of abdominal obesity and that of MS were compared using the Korean National Growth Chart in 2007 (REF2007) and the newly published WC and WHtR reference values in 2022 (REF2022). Results: Both WC and WHtR showed an increasing trend. The prevalence of abdominal obesity was 14.71% based on REF2022, 5.85% points higher than that of 8.86% based on REF2007. MS based on REF2022 had a higher prevalence for both the National Cholesterol Education Program definition (3.90% by REF2007, 4.78% by REF2022) and the International Diabetes Federation definition (2.29% by REF2007, 3.10% by REF2022). The prevalence of both abdominal obesity and MS increased over time. Conclusion: The prevalence of abdominal obesity and MS increased in Korean children and adolescents from 2007 to 2020. When analyzed by REF2022, both abdominal obesity and MS showed higher prevalence rates than when using REF2007, indicating that previous reports were underestimated. Follow-up for abdominal obesity and MS using REF2022 is needed.

Gut bacteria-derived 3-phenylpropionylglycine mitigates adipocyte differentiation of 3T3-L1 cells by inhibiting adiponectin-PPAR pathway.

BACKGROUND: Gut microbiota provide numerous types of metabolites that humans cannot produce and have a huge influence on the host metabolism. Accordingly, gut bacteria-derived metabolites can be employed as a resource to develop anti-obesity and metabolism-modulating drugs. OBJECTIVE: This study aimed to examine the anti-adipogenic effect of 3-phenylpropionylglycine (PPG), which is a glycine conjugate of bacteria-derived 3-phenylpropionic acid (PPA). METHODS: The effect of PPG on preadipocyte-to-adipocyte differentiation was evaluated in 3T3-L1 differentiation models and the degree of the differentiation was estimated by Oil red O staining. The molecular mechanisms of the PPG effect were investigated with transcriptome analyses using RNA-sequencing and quantitative real-time PCR. RESULTS: PPG suppressed lipid droplet accumulation during the adipogenic differentiation of 3T3-L1 cells, which is attributed to down-regulation of lipogenic genes such as acetyl CoA carboxylase 1 (Acc1) and fatty acid synthase (Fasn). However, other chemicals with chemical structures similar to PPG, including cinnamoylglycine and hippuric acid, had little effect on the lipid accumulation of 3T3-L1 cells. In transcriptomic analysis, PPG suppressed the expression of adipogenesis and metabolism-related gene sets, which is highly associated with downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Protein-protein association network analysis suggested adiponectin as a hub gene in the network of genes that were differentially expressed genes in response to PPG treatment. CONCLUSION: PPG inhibits preadipocyte-to-adipocyte differentiation by suppressing the adiponectin-PPAR pathway. These data provide a potential candidate from bacteria-derived metabolites with anti-adipogenic effects.

Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT-NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+-SIRT-FOXO1-melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT-hypothalamic NAD+-FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.

Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c).

Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPRmt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.

Sex-specific bi­directional association between osteoporosis and depression from the national representative data of South Korea.

Both osteoporosis and depression are major health threats, but their interrelationship is not clear. This study elucidated the associations between osteoporosis and depression while considering the temporal sequence of the diagnoses. In this cross-sectional study, data were extracted from the Korean National Health and Nutrition Examination Surveys (2007-2009 and 2015-2019, n = 29,045). Osteoporosis and depression were defined by diagnoses thereof. The odds ratio (OR) of the incident osteoporosis among depression patients without a history of osteoporosis was calculated by multivariable logistic regression adjusted for potential confounders. A reverse association was also assessed. Participants were additionally stratified by their sex and age. As a result, male depression patients aged under 50 years showed higher ORs for osteoporosis than those without depression (OR 9.16, 95% CI 1.78-47.18). Female osteoporosis patients showed lower ORs for depression than those without osteoporosis (OR 0.71, 95% CI 0.58-0.88), especially in women aged 50 years and older. In the sensitivity analysis, the same results were obtained in women by their menopause status. Depression has a strong positive association with the occurrence of osteoporosis in young male adults, and osteoporosis has a negative association with the occurrence of depression in female adults.

Mouse Model of Small for Gestational Age Offspring with Catch-up Growth Failure and Dysregulated Glucose Metabolism in Adulthood.

Background: We aimed to build mouse models of small for gestational age (SGA), recapitulating failure of catch-up growth and dysregulated metabolic outcomes in adulthood. Methods: Pregnant C57BL/6 mice were given a protein-restricted diet (PRD; 6% kcal from protein) during pregnancy without (model 1) or with cross-fostering (model 2). Model 3 extended the PRD to the end of the lactation period. Model 4 changed to a 9% PRD without cross-fostering. Results: Model 1 yielded a reduced size of offspring with a poor survival rate. Model 2 improved survival but offspring showed early catch-up growth. Model 3 maintained a reduced size of offspring after weaning with a higher body mass index and blood glucose levels in adult stages. Model 4 increased the survival of the offspring while maintaining a reduced size and dysregulated glucose metabolism. Conclusion: Models 3 and 4 are suitable for studying SGA accompanying adulthood short stature and metabolic disorders.

Hypothalamic control of energy expenditure and thermogenesis.

Energy expenditure and energy intake need to be balanced to maintain proper energy homeostasis. Energy homeostasis is tightly regulated by the central nervous system, and the hypothalamus is the primary center for the regulation of energy balance. The hypothalamus exerts its effect through both humoral and neuronal mechanisms, and each hypothalamic area has a distinct role in the regulation of energy expenditure. Recent studies have advanced the understanding of the molecular regulation of energy expenditure and thermogenesis in the hypothalamus with targeted manipulation techniques of the mouse genome and neuronal function. In this review, we elucidate recent progress in understanding the mechanism of how the hypothalamus affects basal metabolism, modulates physical activity, and adapts to environmental temperature and food intake changes.

Reference Values for Waist Circumference and Waist-Height Ratio in Korean Children and Adolescents.

Background: Abdominal obesity, which is a strong indicator of cardiometabolic risk, is widely evaluated using waist circumference (WC) and waist-height ratio (WHtR). In Korea, the reference values for WC for children and adolescents were published in 2007 and need to be revised. Moreover, there is no reference for WHtR. The aim of this study was to establish new reference values for WC and WHtR in Korean children and adolescents. Methods: Data of 20,033 subjects from the Korea National Health and Nutrition Examination Survey (2007-2019) were used. Tables for reference values and the graphs of smoothed percentile curves of WC and WHtR for children and adolescents aged 2-18 years by sex were generated using the LMS method and locally estimated scatterplot smoothing regression analysis after removing extreme values. Results: Sex-specific reference tables and percentile curves for WC and WHtR were developed. In the new WC curves, the 10th, 50th, and 90th percentile lines were lower than the corresponding lines of the 2007 reference for both sexes. The WHtR curves showed sex-specific differences, although they demonstrated a relative plateau among those aged ≥10 years in both sexes. In the logistic regression analysis, the WC and WHtR z-scores showed higher odds ratios for predicting cardiometabolic risk factors than the body mass index z-score. Conclusion: New WC and WHtR reference values for Korean children and adolescents aged 2-18 years were developed using the latest statistical methods. These references will help monitor and track WC and WHtR for evaluating abdominal obesity among at-risk children and adolescents in Korea.

Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types.

N6-Methyladenosine (m6A) RNA modification plays a critical role in the posttranscriptional regulation of gene expression. Alterations in cellular m6A levels and m6A-related genes have been reported in many cancers, but whether they play oncogenic or tumor-suppressive roles is inconsistent across cancer types. We investigated common features of alterations in m6A modification and m6A-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort. We calculated m6A writer (W), eraser (E), and reader (R) signatures based on corresponding gene expression. Alterations in the W and E signatures varied according to the cancer type, with a strong positive correlation between the W and E signatures in all types. When the patients were divided according to m6A levels estimated by the ratio of the W and E signatures, the prognostic effect of m6A was inconsistent according to the cancer type. The R and especially the R2 signatures (based on the expression of IGF2BPs) were upregulated in all cancers. Patients with a high R2 signature exhibited poor prognosis across types, which was attributed to enrichment of cell cycle- and epithelial-mesenchymal transition-related pathways. Our study demonstrates common features of m6A alterations across cancer types and suggests that targeting m6A R proteins is a promising strategy for cancer treatment.

Recent Advances in Understanding Peripheral Taste Decoding I: 2010 to 2020.

Taste sensation is the gatekeeper for direct decisions on feeding behavior and evaluating the quality of food. Nutritious and beneficial substances such as sugars and amino acids are represented by sweet and umami tastes, respectively, whereas noxious substances and toxins by bitter or sour tastes. Essential electrolytes including Na+ and other ions are recognized by the salty taste. Gustatory information is initially generated by taste buds in the oral cavity, projected into the central nervous system, and finally processed to provide input signals for food recognition, regulation of metabolism and physiology, and higher-order brain functions such as learning and memory, emotion, and reward. Therefore, understanding the peripheral taste system is fundamental for the development of technologies to regulate the endocrine system and improve whole-body metabolism. In this review article, we introduce previous widely-accepted views on the physiology and genetics of peripheral taste cells and primary gustatory neurons, and discuss key findings from the past decade that have raised novel questions or solved previously raised questions.

Effects of Intermittent Fasting on the Circulating Levels and Circadian Rhythms of Hormones.

Intermittent fasting has become an increasingly popular strategy in losing weight and associated reduction in obesity-related medical complications. Overwhelming studies support metabolic improvements from intermittent fasting in blood glucose levels, cardiac and brain function, and other health benefits, in addition to weight loss. However, concerns have also been raised on side effects including muscle loss, ketosis, and electrolyte imbalance. Of particular concern, the effect of intermittent fasting on hormonal circadian rhythms has received little attention. Given the known importance of circadian hormonal changes to normal physiology, potential detrimental effects by dysregulation of hormonal changes deserve careful discussions. In this review, we describe the changes in circadian rhythms of hormones caused by intermittent fasting. We covered major hormones commonly pathophysiologically involved in clinical endocrinology, including insulin, thyroid hormones, and glucocorticoids. Given that intermittent fasting could alter both the level and frequency of hormone secretion, decisions on practicing intermittent fasting should take more considerations on potential detrimental consequences versus beneficial effects pertaining to individual health conditions.

Increments of alpha-dystroglycan expression in liver metastasis correlate with poor survival in gastric cancer.

BACKGROUND: Dystroglycan (DG) is a recently focused adhesion molecule with possible roles in cancer development and progression. We investigated correlations between alpha-DG expression and prognosis in gastric carcinoma with liver metastasis. METHODS: For 40 patients with gastric adenocarcinoma and liver-only metastasis, alpha-DG expression was determined by immunohistochemistry in paraffin-embedded surgical specimens of resected stomach tumor, resected liver metastasis, and their normal counterpart tissues. Correlations between alpha-DG expression and prognosis were retrospectively analyzed. RESULTS: alpha-DG expression was higher in primary gastric cancer (P = 0.006) and lower in liver metastasis (P = 0.002) than in each normal counterpart. In primary stomach cancer, patients who had lower alpha-DG expression in tumors than in normal counterparts showed poor overall survival (OS) (P = 0.028). In contrast, in the liver, patients who had higher alpha-DG expression in tumors than in normal counterparts showed poor OS (P = 0.022). Also, higher alpha-DG expression in liver metastasis than in stomach tumors led to poor recurrence-free survival (P = 0.023) and OS (P = 0.056). CONCLUSIONS: This approach may be used to further understanding of the pathogenesis of liver metastasis from gastric cancer. Further studies are warranted to reveal the mechanisms of alpha-DG dysregulation in liver metastasis.