Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases. Abbreviations: ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.

Thyroid dysfunction has been implicated as a potential pathophysiological factor in glucose homeostasis and insulin resistance (IR). This study aimed to identify the correlation between thyroid dysfunction and IR. We used data from the sixth Korean National Health and Nutrition Examination Survey to evaluate a total of 5727 participants. The triglyceride glucose (TyG) index and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated to represent IR. Correlation analysis was performed between thyroid dysfunction and IR. The log-transformed TSH (LnTSH) and free T4 were significantly correlated with the TyG index (TSH, beta coefficient 0.025, 95% confidence interval [CI] 0.014–0.036, p < 0.001; free T4, − 0.110 (− 0.166 to − 0.054), p < 0.001) but not HOMA-IR. Overt hypothyroidism is correlated with increased TyG index in pre-menopausal females (0.215 (0.122–0.309) p < 0.001). On the other hand, overt hyperthyroidism is correlated with increased HOMA-IR in males (0.304 (0.193–0.416), p < 0.001) and post-menopausal females (1.812 (1.717–1.907), p < 0.001). In euthyroid subjects, LnTSH and TyG index were significantly correlated in females. In conclusion, both hyperthyroidism and hypothyroidism might be associated with IR but by different mechanisms. It might be helpful to assess IR with appropriate indexes in patients with thyroid dysfunction.

Aims: The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium‐glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 diabetes mellitus. Materials and Methods: Patients with glycated haemoglobin (HbA1c) of 7.0‐10.0%, entered a 2‐week placebo run‐in period, and were randomized to receive once‐daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12. Results: Overall, 194 patients were included in the full analysis set [placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49)]. Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (−0.79%, −0.89%, −0.92% and −0.08%, respectively; p < .001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were −30.5, −31.1, −35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c 0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups. Conclusions: Once‐daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well‐tolerated treatment for Korean patients with type 2 diabetes mellitus.

Background: Graves' disease (GD) is an autoimmune thyroid disorder caused by antibodies stimulating the thyrotropin (TSH) receptor. TSH receptor antibody (TRAb) measurement is useful for predicting GD relapse after antithyroid drug (ATD) treatment. However, the association of other thyroid autoantibodies with GD relapse remains obscure. Methods: This retrospective study enrolled patients with GD who were initially treated with ATD. TRAb, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured at the initial diagnosis and at the time of ATD discontinuation. Results: A total of 55 patients were enrolled. The mean age was 49.7 years, and 39 patients (70.9%) were female. Antibody positivity at diagnosis was 90.9%, 69.1%, and 61.9% for TRAb, TPOAb, TgAb, respectively. Median ATD treatment period was 15.1 months. At the time of ATD withdrawal, TRAb titers decreased uniformly overall. Conversely, TPOAb and TgAb showed various changes. After withdrawal of ATD, 19 patients (34.5%) experienced relapse. No clinical features or laboratory results were significantly related to relapse in the overall patient group. However, in the TPOAb positive group at diagnosis, increasing titer of TPOAb or TgAb after ATD treatment was significantly and independently related to relapse free survival (TPOAb: hazard ratio [HR], 17.99; 95% confidence interval [CI], 1.66 to 195.43; P=0.02) (TgAb: HR, 5.73; 95% CI, 1.21 to 27.26; P=0.03). Conclusion: Changes in TPOAb or TgAb titers during treatment might be useful for predicting relapse after ATD treatment in patients with positive TPOAb at diagnosis.

In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.

To investigate associations of glomerular hyperfiltration with other metabolic factors in a nationally representative dataset. We analyzed cross-sectional data from 15,918 subjects with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m² and urine albumin creation ratio (ACR) <30 mg/g, who participated in the 5th and 6th Korea National Health and Nutrition Examination Surveys. Hyperfiltration was defined as eGFR (CKD-EPI equation) exceeding the age- and sex-specific 95th percentile for healthy control subjects. Prevalence of hyperfiltration was 5.2% and that among normal, prediabetic, and diabetic subjects was 4.9%, 5.6%, and 7.3%, respectively, after adjusting for age, sex, and body weight (p for trend = 0.008). In a multiple logistic regression analysis, hyperfiltration was associated with a body mass index ≥30 kg/m² [odds ratio (OR) = 3.461, p<0.001], waist circumference 85 cm (men) or 80 cm (women) (OR = 1.425, p = 0.015), systolic blood pressure 120–129 mmHg (OR = 1.644, p = 0.022), fasting plasma glucose 140 mg/dL (OR = 1.695, p = 0.033) and t serum triglyceride level 500 mg/dL (OR = 2.988, p = 0.001), and was independently associated with the ACR (B = 0.053, p<0.001). In a general Korean population, both hyperfiltration and ACR were associated with similar metabolic parameters, and hyperfiltration correlated independently with a high ACR. Longitudinal studies are needed to further explore risks of hyperfiltration and microalbuminuria.