Probes for INSULIN

The arcuate nucleus of the hypothalamus is central in the regulation of body weight homeostasis through its ability to sense peripheral metabolic signals and relay them, through neural circuits, to other brain areas, ultimately affecting physiological and behavioural changes. The early postnatal development of these neural circuits is critical for normal body weight homeostasis, such that perturbations during this critical period can lead to obesity. The role for peripheral regulators of body weight homeostasis, including leptin, insulin and ghrelin, in this postnatal development is well described, yet some of the fundamental processes underpinning axonal and dendritic growth remain unclear. Here, we hypothesised that molecules known to regulate axonal and dendritic growth processes in other areas of the developing brain would be expressed in the postnatal arcuate nucleus and/or target nuclei where they would function to mediate the development of this circuitry. Using state-of-the-art RNAscope technology, we have revealed the expression patterns of genes encoding Dcc/Netrin-1, Robo1/Slit1 and Fzd5/Wnt5a receptor/ligand pairs in the early postnatal mouse hypothalamus. We found that individual genes had unique expression patterns across developmental time in the arcuate nucleus, paraventricular nucleus of the hypothalamus, ventromedial nucleus of the hypothalamus, dorsomedial nucleus of the hypothalamus, median eminence and, somewhat unexpectedly, the third ventricle epithelium. These observations indicate a number of new molecular players in the development of neural circuits regulating body weight homeostasis, as well as novel molecular markers of tanycyte heterogeneity.

MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID-19. However, how SARS-CoV-2 alters the progression of chronic diseases remain unclear. We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice. SARS-CoV-2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis. Pre-existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling. We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases. Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection, which further aggravated the pre-existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.

tRF-28-QSZ34KRQ590K demonstrated a significant diagnostic value for AD in the ROC curve analysis. There were 28 target genes of tRF-28-QSZ34KRQ590K, including tachykinin receptor 1, RANBP2-like and GRIP domain-containing 1, non-SMC condensin I complex subunit H (NCAPH), ectodysplasin-A receptor, contactin-associated protein family member 5, cytochrome P450 family (CYP)27 subfamily C member 1, WD repeat domain 33, POTE ankyrin domain family member F, insulin receptor substrate 1, thyroid hormone receptor interactor 12, S-antigen visual arrestin, ATPase plasma membrane Ca2+ transporting 2, neurexophilin and PC-esterase domain family member 3, Rho GTPase activating protein 31, p21 (RAC1)-activated kinase 2, midnolin, unc-13 homolog A, potassium channel tetramerization domain containing 15, endogenous retrovirus group V member 1 envelope, zinc finger and SCAN domain containing 18, KIAA0930 (also known as C22orf9, LSC3), SET binding factor 1, forkhead box K1, AVL9 cell migration-associated, FKBP prolyl isomerase family member 6, X-ray repair cross complementing 2, phosphatase and actin regulator 1 and mitochondrial calcium uniporter regulator 1. A previous study reported on a pediatric patient with AD, mental retardation, autistic features, epilepsy, developmental delay and abnormal immunological results, who carried a 7.9 Mb de novo deletion of chromosome 22q13.2/qter, a region containing the NCAPH2, SH3 and multiple ankyrin repeat domains 3 and CYP2D6 genes (26). These genes are associated with the T-cell immune response and the inflammatory response has also been suggested to have roles in the pathogenesis of AD. Thus, tRF-28-QSZ34KRQ590K may be involved in the pathogenesis of AD by affecting the inflammatory response. Further studies are required to uncover the role of tRF-28-QSZ34KRQ590K in the pathogenesis of AD. At present, it remains undetermined whether tRF-28-QSZ34KRQ590K is specifically expressed in AD, although it has not been reported to be expressed in any other diseases, to the best of our knowledge. However, tRF-28-QSZ34KRQ590K exhibited a significant diagnostic value in the ROC curve analysis, which suggested that tRF-28-QSZ34KRQ590K may be a potential biomarker for pediatric patients with AD, although further studies are required to confirm the role of this tRF in AD.