Hyemi Shin

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ–TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo–YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Purpose: To compare the long-term clinical outcomes of patients with refractive accommodative esotropia (RAET) and infantile esotropia (IET). Methods: The medical records of patients with RAET and IET who were followed-up for more than 36 months were retrospectively analyzed. The RAET patients were prescribed spectacles to correct cycloplegic refraction and those with IET underwent bilateral, medial rectus recession. Visual acuity, refraction, the angle of esodeviation at far and near distances, and near-stereopsis were measured at each visit. The IET patients were divided into two groups by the time of surgery (before and after 24 months of age). Patients in both groups who underwent reoperations after diagnosis of partially accommodative esotropia (PAET) and recurrent IET during follow-up were analyzed. Results: Sixty-nine patients (40 with RAET and 29 with IET) were included. The follow-up period was 69.48 ± 28.41 months. At the final visit, the angles of esodeviation were 2.82 ± 5.46 prism diopters (PD) in the RAET group and 9.28 ± 8.37 PD in the IET group (p < 0.01). In IET patients who underwent surgery before and after 24 months of age, the angles of esodeviation were 4.62 ± 5.25 and 13.06 ± 8.63 PD and the median near-stereopsis values 60 and 140 arcsec at the final visit (p < 0.01, 0.03). Seven patients (17.5%) in the RAET group, and 2 (15.4%) and 10 (62.5%) IET patients who underwent surgery before and after 24 months of age, required reoperations (p < 0.01). Conclusions: RAET and IET patients who underwent surgery before 24 months of age exhibited better alignment and stereopsis at the final visit than those who underwent later surgery and the reoperation rate was lower.

Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.

Secretory proteins are an essential component of interorgan communication networks that regulate animal physiology. Current approaches for identifying secretory proteins from specific cell and tissue types are largely limited to in vitro or ex vivo models which often fail to recapitulate in vivo biology. As such, there is mounting interest in developing in vivo analytical tools that can provide accurate information on the origin, identity, and spatiotemporal dynamics of secretory proteins. Here, we describeiSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which selectively labels proteins that transit through the classical secretory pathway via catalytic actions of Sec61b-TurboID, a proximity labeling enzyme anchored in the ER lumen. To validateiSLET in a whole-body system, we expressiSLET in the mouse liver and demonstrate efficient labeling of liver secretory proteins which could be tracked and identified within circulating blood plasma. Furthermore, proteomic analysis of the labeled liver secretome enriched from liveriSLET mouse plasma is highly consistent with previous reports of liver secretory protein profiles. Taken together,iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.

In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.

Here we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which labels secretory pathway proteins as they transit through the ER-lumen to enable dynamic tracking of tissue-specific secreted proteomes in vivo. We expressed iSLET in the mouse liver and demonstrated efficient in situ labeling of the liver-specific secreted proteome which could be tracked and identified within circulating blood plasma. iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.

Here we describe i SLET ( i n situ S ecretory protein L abeling via E R-anchored T urboID) which labels secretory pathway proteins as they transit through the ER-lumen to enable dynamic tracking of tissue-specific secreted proteomes in vivo . We expressed i SLET in the mouse liver and demonstrated efficient in situ labeling of the liver-specific secreted proteome which could be tracked and identified within circulating blood plasma. i SLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.