Endocrinology
Abstract
Maternal hyperthyroidism is associated with an increased incidence of congenital abnormalities at birth, but it is not clear which of those defects arise from a transient developmental excess of thyroid hormone, and which depend on pregnancy stage, antithyroid drug choice, or unwanted subsequent fetal hypothyroidism. To address this issue we studied a mouse model of comprehensive developmental thyrotoxicosis secondary to a lack of type 3 deiodinase (DIO3). Dio3-/- mice exhibit reduced neonatal viability on most genetic backgrounds and perinatal lethality on a C57BL/6 background. Dio3-/- mice exhibit severe growth retardation during the neonatal period and cartilage loss. Mice surviving after birth manifest brain and cranial dysmorphisms, severe hydrocephalus, choanal atresia, and cleft palate. These abnormalities are noticeable in C57BL/6J Dio3-/- mice at fetal stages, in addition to a thyrotoxic heart with septal defects and thin ventricular walls. Our findings stress the protecting role of DIO3 during development and support the hypothesis that human congenital abnormalities associated with hyperthyroidism during pregnancy are caused by transient thyrotoxicosis before clinical intervention. Our results also suggest thyroid hormone involvement in the etiology of idiopathic pathologies including cleft palate, choanal atresia, Chiari malformations, Kaschin-Beck disease, and Temple and other cranio-encephalic and heart syndromes.
Authors
M. Elena Martinez, Ilka Pinz, Marilena Preda, Christine R. Norton, Thomas Gridley, Arturo Hernandez
Abstract
Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell–derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC–derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.
Authors
Rie Asada Kitamura, Kristina G. Maxwell, Wenjuan Ye, Kelly Kries, Cris M. Brown, Punn Augsornworawat, Yoel Hirsch, Martin M. Johansson, Tzvi Weiden, Joseph Ekstein, Joshua Cohen, Justin Klee, Kent Leslie, Anton Simeonov, Mark J. Henderson, Jeffrey R. Millman, Fumihiko Urano
Abstract
Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children insulin resistance persists leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here we show that puberty is associated with a transient increase in β-cell proliferation in rats and humans of both sexes. In rats, β-cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β-cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-HT) pathway underwent changes consistent with proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2B blocked the increase in β-cell proliferation in pubertal islets ex vivo and in vivo. Peri-pubertal metabolic stress blunted β-cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GHR/5-HT/HTR2B signaling in the control of β-cell mass expansion during puberty and a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.
Authors
Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout
Abstract
Biased agonism is a frontier field in G-protein coupled receptor (GPCR) research. Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calcium-sensing receptor (CaSR) autoantibodies, to date, showing either simple blocking or biased properties (i.e., stimulatory or blocking effects on different downstream signaling pathways). This emphasizes the importance of the Gi/o (pertussis toxin-sensitive G proteins, whose βγ subunits activate multiple signals including ERK1/2) in regulating PTH secretion. We here describe three patients with symptomatic AHH that shared characteristics with the two cases we previously reported as follows: [1] aged (between 74-87 years at diagnosis); [2] male; [3] unexpectedly showed no other autoimmune diseases; [4] showed spontaneously fluctuating calcium levels from approximately normal to near fatally high ranges; [5] acute exacerbations could be successfully treated with prednisolone and/or calcimimetics; [6] the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR; and that [7] were likely to be conformational (i.e., recognizing and thereby stabilizing a unique active conformation of CaSR that activates Gq/11, activating phosphatidylinositol turnover, but not Gi/o). Our observations with these prominent commonalities may provide new insights into the phenotype and characteristics of AHH and the mechanisms by which the biased agonism of GPCRs operate.
Authors
Noriko Makita, Junichiro Sato, Katsunori Manaka, Kimiko Akahane, Takahiro Ito, Hajime Yamazaki, Akira Mizoguchi, Yusuke Hikima, Hirofumi Horikoshi, Masaomi Nangaku, Taroh Iiri
Abstract
The liver regulates energy partitioning and utilization in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor-21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate utilization to reduce hepatic lipid storage. Here we report that FGF21 alters hepatic transcriptional and metabolic responses, and reduces liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor --> cAMP --> EPAC1 signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent, old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex, but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.
Authors
Aki T. Chaffin, Karlton R. Larson, Kuei-Pin Huang, Chih-Ting Wu, Nadejda Godoroja, Yanbin Fang, Devi Jayakrishnan, Karla A. Soto Sauza, Landon C. Sims, Niloufar Mohajerani, Michael L. Goodson, Karen K. Ryan
Abstract
In rodent models of type 2 diabetes (T2D), central administration of fibroblast growth factor 1 (FGF1) normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons, and if so whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here we show that FGF1 inhibits ARC NPY/AgRP neuron activity, both after icv injection in vivo and when applied ex vivo in a slice preparation, and that the underlying mechanism involves increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons is also highly durable, lasting for at least two weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by icv FGF1 injection in rodent models of T2D.
Authors
Eunsang Hwang, Jarrad M. Scarlett, Arian F. Baquero, Camdin Bennett, Yanbin Dong, Dominic Chau, Jenny M. Brown, Aaron J. Mercer, Thomas H. Meek, Kevin L. Grove, Bao Anh N. Phan, Gregory J. Morton, Kevin W. Williams, Michael W. Schwartz
Abstract
Inactivating mutations of ARMC5 are responsible for the development of bilateral macronodular adrenal hyperplasia (BMAH). Although ARMC5 inhibits adrenocortical tumor growth and is considered as tumor-suppressor gene, its molecular function is poorly understood. In this study, through biochemical purification using SREBF (SREBP) as bait, we identified the interaction between SREBF and ARMC5 through its Armadillo repeat. We also found that ARMC5 interacted with CUL3 through its BTB domain and underwent self-ubiquitination. ARMC5 colocalized with SREBF1 in the cytosol and induced proteasome-dependent degradation of full-length SREBF through ubiquitination. Introduction of missense mutations in Armadillo repeat of ARMC5 attenuated the interaction between SREBF, and introduction of mutations found in BMAH completely abolished its ability to degrade full-length SREBF. In H295R adrenocortical cells, silencing of ARMC5 increased full-length SREBFs and upregulated SREBF2 target genes. siARMC5-mediated cell growth was abrogated by simultaneous knockdown of SREBF2 in H295R cells. Our results demonstrated that ARMC5 was a substrate adaptor protein between full-length SREBF and CUL3-based E3 ligase, and suggested the involvement of SREBF pathway in the development of BMAH.
Authors
Yosuke Okuno, Atsunori Fukuhara, Michio Otsuki, Iichiro Shimomura
Abstract
Adaptation to increased insulin demand is mediated by β-cell proliferation and neogenesis among other mechanisms. Although it is known that pancreatic β-cells can arise from ductal progenitors, these observations have been limited mostly to the neonatal period. We have recently reported that the duct is a source of insulin secreting cells in adult insulin resistant states. To further explore the signaling pathways underlying the dynamic β-cell reserve during insulin resistance we undertook human islet and duct transplantations under the kidney capsule of immunodeficient NOD SCID gamma (NSG) mouse models that were either pregnant, insulin resistant or had insulin resistance superimposed upon pregnancy (pregnancy+insulin resistance), followed by single-nucleus RNA-sequencing (snRNA-seq) on snap-frozen graft samples. We observed an upregulation of proliferation markers (e.g., NEAT1), expression of islet endocrine cell markers (e.g., GCG and PPY) as well as mature β-cell markers (e.g., INS), in transplanted human duct grafts in response to high insulin demand. We also noted downregulation of ductal cell identity genes (e.g., KRT19 and ONECUT2) coupled with upregulation of β-cell development and insulin signaling pathways. These results indicate that subsets of ductal cells are able to gain β-cell identity and reflect a form of compensation during the adaptation to insulin resistance in both physiological and pathological states.
Authors
Ercument Dirice, Giorgio Basile, Sevim Kahraman, Danielle Diegisser, Jiang Hu, Rohit N. Kulkarni
Abstract
The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.
Authors
Xintao Qiu, Lisha G. Brown, Jennifer L. Conner, Holly M. Nguyen, Nadia Boufaied, Sarah Abou Alaiwi, Ji-Heui Seo, Talal El Zarif, Connor Bell, Edward O’Connor, Brian Hanratty, Mark Pomerantz, Matthew L. Freedman, Myles Brown, Michael C. Haffner, Peter S. Nelson, Felix Y. Feng, David P. Labbé, Henry W. Long, Eva Corey
Abstract
Insulin secretion from pancreatic β cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that β cell–specific deletion of Zfp148 (β-Zfp148KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from β‑Zfp148KO and control mice fed both a chow and a Western-style diet. β-Zfp148KO islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels. β-Zfp148KO islets also exhibited elevated sensitivity to amino acid–induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate-dependent (PEP-dependent), ATP-sensitive K+ channel closure, independent of glycolysis. RNA-Seq and proteomics of β-Zfp148KO islets revealed altered levels of enzymes involved in amino acid metabolism (specifically, SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, and PSAT1) and intermediary metabolism (namely, GOT1 and PCK2), consistent with altered PEP cycling. In agreement with this, β-Zfp148KO islets displayed enhanced insulin secretion in response to l-glutamine and activation of glutamate dehydrogenase. Understanding pathways controlled by ZFP148 may provide promising strategies for improving β cell function that are robust to the metabolic challenge imposed by a Western diet.
Authors
Christopher H. Emfinger, Eleonora de Klerk, Kathryn L. Schueler, Mary E. Rabaglia, Donnie S. Stapleton, Shane P. Simonett, Kelly A. Mitok, Ziyue Wang, Xinyue Liu, Joao A. Paulo, Qinq Yu, Rebecca L. Cardone, Hannah R. Foster, Sophie L. Lewandowski, José C. Perales, Christina M. Kendziorski, Steven P. Gygi, Richard G. Kibbey, Mark P. Keller, Matthias Hebrok, Matthew J. Merrins, Alan D. Attie
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