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Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark feature of NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet-fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet-fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH., Introduction The liver is the principal organ involved in lipid metabolism. Dyslipidemia leads to metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), which has become an increasing global public [...]

Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states., Introduction At pubertal onset, the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator becomes activated to trigger the hormonal cascade necessary for sexual maturation. It has been estimated that 50%-80% of the [...]

Resistance to thyroid hormone (RTH) is most often due to point mutations in the [beta]-isoform of the thyroid hormone (TH) receptor (TR-[beta]). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-[beta] locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded [T.sub.3] replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T3 treatment failed to normally suppress these levels. [T.sub.3] treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after [T.sub.3] treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH. corepressor | homodimer | negative regulation | resistance to thyroid hormone

Author(s): Xiao Yan Zhou [1, 2]; Nobuyuki Shibusawa [1, 2]; Karuna Naik [1]; Delia Porras [1]; Karla Temple [1]; Hesheng Ou [1]; Kelly Kaihara [1]; Michael W Roe [1]; Matthew [...]

Giving thyroid cancer patients recombinant thyrotropin instead of withdrawing thyroid hormone may not result in an accurate thyroid scan. Thyroid scans are normally done with radioactive iodine to see if these patients have any residual cancer. But the thyroid gland must be stimulated to take up the iodine and this is done by temporarily discontinuing thyroid hormone treatment. Researchers gave 120 cancer patients undergoing a thyroid scan recombinant human thyrotropin so the patients could continue taking thyroid hormone. The scans were not as accurate but the patients had fewer episodes of hypothyroidism and mood disorders.

Members of the ErbB family of cell surface tyrosine kinase receptors are important targets for cancer treatment because they frequently contribute to the pathogenesis of malignancy. In this issue of the JCI, Fukuoka et al. generate data that suggest that using a tyrosine kinase inhibitor (TKI) against epidermal growth factor receptor (EGFR; also known as ErbB1) may be a novel approach for treating patients with hypercortisolemia due to pituitary corticotroph adenomas (Cushing disease). While surgical resection remains the cornerstone of treatment for individuals with such tumors, this study suggests that TKIs could perhaps be used to reduce tumor size prior to surgery or to treat recurrent disease after surgery., Cushing disease is a condition in which the pituitary gland releases too much adrenocorticotropic hormone (ACTH), the hormone that stimulates the secretion of cortisol from the adrenal cortex (Figure 1 [...]

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Mutations in the gene encoding Pit-1 have been found in two dwarf mouse strains displaying hypoplasia of growth hormone, prolactin, and thyroid-stimulating, hormone-secreting cell types in the anterior pituitary. A point mutation in this gene was identified on one allele in a patient with combined pituitary hormone deficiency. Mutant Pit-1 binds DNA normally but acts as a dominant inhibitor of Pit-1 action in the pituitary., Pit-1-growth hormone factor-1 (Pit-1) is a member of the POU family of transcription factors that regulate mammalian development (1). Pit-1 contains two protein domains, termed POU-specific and POU-homeo, which are [...]

Congenital hypothyroidism and the thyroid hormone ([T.sub.3]) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a [T.sub.3] binding mutation was introduced into the mouse TR-[Beta] locus by homologous recombination. Because of this [T.sub.3] binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.