Anorexia and weight loss are prevalent in infectious diseases. To investigate the molecular mechanisms underlying these phenomena, we established animal models of infection-associated anorexia by administrating bacterial and viral products, lipopolysaccharide (LPS) and human immunodeficiency virus-1 transactivator protein (Tat). In these models, we found that the nuclear factor-B (NF-B), a pivotal transcription factor for inflammation-related proteins, was activated in the hypothalamus. In parallel, administration of LPS and Tat increased hypothalamic pro-inflammatory cytokine production, which was abrogated by inhibition of hypothalamic NF-B. In vitro, NF-B activation directly stimulated the transcriptional activity of proopiomelanocortin (POMC), a precursor of anorexigenic melanocortin, and mediated the stimulatory effects of LPS, Tat, and pro-inflammatory cytokines on POMC transcription, implying the involvement of NF-B in controlling feeding behavior. Consistently, hypothalamic injection of LPS and Tat caused a significant reduction in food intake and body weight, which was prevented by blockade of NF-B and melanocortin. Furthermore, disruption of IB kinase-, an upstream kinase of NF-B, in POMC neurons attenuated LPS-and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-B activation in hypothalamic POMC neurons. In addition, hypothalamic NF-B was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-B also serves as a downstream signaling pathway of leptin.
SUMMARY Activation of inositol-requiring enzyme (IRE1α) is an indispensable step in remedying the cellular stress associated with lipid perturbation in the endoplasmic reticulum (ER) membrane. IRE1α is a single-spanning ER transmembrane protein possessing both kinase and endonuclease functions, and its activation can be fully achieved through the dimerization and/or oligomerization process. How IRE1α senses membrane lipid saturation remains largely unresolved. Using both computational and experimental tools, we systematically investigated the dimerization process of the transmembrane domain (TMD) of IRE1α and found that, with help of the serine 450 residue, the conserved tryptophan 457 residue buttresses the core dimerization interface of IRE1α-TMD. BiFC (bimolecular fluorescence complementation) experiments revealed that mutation on these residues abolished the saturated fatty acid-induced dimerization in the ER membrane and subsequently inactivated IRE1α activity in vivo. Therefore, our results suggest that the structural elements of IRE1α-TMD serve as a key sensor that detects membrane aberrancy.
Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes).In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic -cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2 ؉/؊ mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2 ؉/؊ mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2 ؉/؊ islets. These results suggest that ASC-2 regulates insulin secretion and -cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.Type 2 diabetes is the most common form of diabetes and is a disorder of glucose homeostasis resulting from insulin resistance and relative insulin deficiency (52). Insulin secretion is affected by metabolic signals and transcription factors that are necessary for proper differentiation and growth of various types of pancreatic islet cells (10). The main intracellular signals for insulin secretion derive from glucose metabolism. Glucose metabolism generates oscillations in the ATP/ADP ratio, which lead to the opening and closing of ATP-sensitive K ϩ channels and produce subsequent oscillations in membrane potential, cytoplasmic calcium concentration, and insulin release (7).Studies of human mutations and knockout mice revealed several transcription factors that play crucial roles in pancreatic development, such as PDX-1 (also known as IPF-1) (21), Nkx2.2 (50), Pax4 (47), neurogenin3 (15), and NeuroD (40). The significance of transcription factors in pancreatic development was further reinforced by the analysis of mutations in patients with maturity-onset diabetes of the young (MODY).MODY is a monogenic type of diabetes characterized by early onset, autosomal dominant inheritance and impaired insulin secretion. Although the MODY2 gene encodes a glucokinase specific to the liver and -cells (3), the remaining five MODY genes encode the transcription factors hepatic nuclear factor
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