Interorgan crosstalk via secreted hormones and metabolites is a fundamental aspect of mammalian metabolic physiology. Beyond the highly specialized endocrine cells, peripheral tissues are emerging as an important source of metabolic hormones that influence energy and nutrient metabolism and contribute to disease pathogenesis. Neuregulin 4 (Nrg4) is a fat-derived hormone that protects mice from nonalcoholic steatohepatitis (NASH) and NASH-associated liver cancer by shaping hepatic lipid metabolism and the liver immune microenvironment. Despite its enriched expression in brown fat, whether NRG4 plays a role in thermogenic response and mediates the metabolic benefits of cold exposure remain unexplored. Here we show that Nrg4 expression in inguinal white adipose tissue (iWAT) is highly responsive to chronic cold exposure. Nrg4 deficiency impairs beige fat induction and renders mice more susceptible to diet-induced metabolic disorders under mild cold conditions. Using mice with adipocyte and hepatocyte-specific Nrg4 deletion, we reveal that adipose tissue-derived NRG4, but not hepatic NRG4, is essential for beige fat induction following cold acclimation. Furthermore, treatment with recombinant NRG4-Fc fusion protein promotes beige fat induction in iWAT and improves metabolic health in diet-induced obese mice. These findings highlight a critical role of NRG4 in mediating beige fat induction and preserving metabolic health under mild cold conditions.
Zhimin Chen, Peng Zhang, Tongyu Liu, Xiaoxue Qiu, Siming Li, Jiandie D. Lin
BACKGROUND Alcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODS This is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTS In the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33–53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52–0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSION These results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATION ClinicalTrials.gov NCT03204396.FUNDING Swiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.
Leila Probst, Sophie Monnerat, Deborah R. Vogt, Sophia Lengsfeld, Thilo Burkard, Andrea Meienberg, Cemile Bathelt, Mirjam Christ-Crain, Bettina Winzeler
HNF1A haploinsufficiency underlies the most common form of human monogenic diabetes (HNF1A-MODY) and hypomorphic HNF1A variants confer type 2 diabetes risk, but a lack of experimental systems for interrogating mature human islets has limited our understanding of how the transcription factor HNF1α regulates adult islet function. Here, we combined conditional genetic targeting in human islet cells, RNA sequencing, chromatin mapping with Cleavage Under Targets & Release Using Nuclease (CUT&RUN), and transplantation-based assays to determine HNF1α-regulated mechanisms in adult human pancreatic α and β cells. Short hairpin RNA-mediated (shRNA) suppression of HNF1A in primary human pseudoislets led to blunted insulin output and dysregulated glucagon secretion after transplantation in mice, recapitulating phenotypes observed in diabetic patients. These deficits corresponded with altered expression of genes encoding factors critical for hormone secretion, including calcium channel subunits, ATPase transporters and extracellular matrix constituents. Additionally, HNF1A loss led to upregulation of transcriptional repressors, providing evidence for a mechanism of transcriptional de-repression through HNF1α. CUT&RUN mapping of HNF1α DNA-binding sites in primary human islets imputed a subset of HNF1α-regulated genes as direct targets. These data elucidate mechanistic links between HNF1A loss and diabetic phenotypes in mature human α and β cells.
Mollie F. Qian, Romina J. Bevacqua, Vy M.N. Coykendall, Xiong Liu, Weichen Zhao, Charles A. Chang, Xueying Gu, Xiao-Qing Dai, Patrick E. MacDonald, Seung K. Kim
Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, but their effects on cortical bone may differ. Little is known about their differential effects on osteocytes. We compared cortical osteocyte and skeletal responses to ABL and TPTD in sham-operated and ovariectomized mice. Administered 7 weeks after ovariectomy for 4 weeks at a dose of 40 μg/kg/d, TPTD and ABL had similar effects on trabecular bone, but ABL showed stronger effects in cortical bone. In cortical osteocytes, both treatments decreased lacunar area, reflecting altered peri-lacunar remodeling favoring matrix accumulation. Osteocyte RNA-Seq revealed that several genes and pathways were altered by ovariectomy and affected similarly by TPTD and ABL. Notwithstanding, several signaling pathways were uniquely regulated by ABL. Thus, in mice, TPTD and ABL induced a positive osteocyte peri-lacunar remodeling balance, but ABL induced stronger cortical responses and affected the osteocyte transcriptome differently. We concluded that ABL affected the cortical osteocyte transcriptome in a manner subtly different from TPTD, resulting in more beneficial remodeling/modeling changes and homeostasis of the cortex.
Zhengtao Lv, Jiaming Zhang, Shuang Liang, Chenhe Zhou, Dorothy Hu, Daniel J. Brooks, Mary L. Bouxsein, Beate Lanske, Paul Kostenuik, Francesca Gori, Roland Baron
Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here we studied human iPSC-derived hepatic organoids and identified a robust induction in DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in D2-T3 per-sists until the hepatoblasts differentiate into hepatocytes- or cholangiocytes-like cells, nei-ther of which express DIO2. Preventing the induction of the D2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by 60%, and increased the number of cholangiocyte-like cells by 55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not ful-ly restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in D2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implica-tions for how the liver handles energy substrates.
Jorge Hidalgo-Álvarez, Federico Salas-Lucia, Diana Vera Cruz, Tatiana L. Fonseca, Antonio C. Bianco
In youth with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on beta cell function and insulin sensitivity. Youths with obesity and 2-h glucose≥120mg/dL underwent a 3-h OGTT and an isoglycemic intravenous glucose infusion to quantify the incretin effect. After 2 years, 30/39 participants had a repeated OGTT and were stratified into three tertiles according to the baseline incretin effect. Thirty participants completed the baseline and follow-up tests. The high-incretin effect group demonstrated a longitudinal increase in beta cell function (DIMM) (p=0.034), with greater insulin sensitivity at follow-up (p=0.034) and stable insulin secretion (φtotal) (p=0.077). A lower incretin effect at baseline was associated with a higher 1-h and 2-h glucose at follow-up (r = -0.558, p=0.001 and r = -0.533, p=0.004). The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline (p=0.008 and p=0.029), while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin respect to the high-incretin group (p=0.049).
Alfonso Galderisi, Domenico Tricò, Jessica O. Lat, Stephanie L. Samuels, Ram Weiss, Michelle Van Name, Bridget Pierpont, Nicola Santoro, Sonia Caprio
Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures and neurologic abnormalities (PASNA) as well as in autism spectrum disease. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization show elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone:renin ratio and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induces tonic-clonic seizures. Neurologic abnormalities include hyperlocomotion, impaired performance in the rotarod test, impaired nest building and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels and rotarod performance respond to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.
Gabriel Stölting, Hoang An Dinh, Marina Volkert, Nicole Hellmig, Julia Schewe, Luise Hennicke, Eric Seidel, Herbert Oberacher, Junhui Zhang, Richard P. Lifton, Iris Urban, Melissa Long, Marion Rivalan, Timothy Nottoli, Ute I. Scholl
Intact fibroblast growth factor 23 (iFGF23) is a phosphaturic hormone that is cleaved by furin into N-terminal and C-terminal fragments. Several studies have implicated vitamin D in regulating furin in infections. Thus, we investigated the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] and the vitamin D receptor (VDR) on furin-mediated iFGF23 cleavage. Mice lacking VDR (Vdr–/–) had a 25-fold increase in iFGF23 cleavage, with increased furin levels and activity compared with wild-type (WT) littermates. Inhibition of furin activity blocked the increase in iFGF23 cleavage in Vdr–/– animals and in a Vdr-knockdown osteocyte OCY454 cell line. Chromatin immunoprecipitation revealed VDR binding to DNA upstream of the Furin gene, with more transcription in the absence of VDR. In WT mice, furin inhibition reduced iFGF23 cleavage, increased iFGF23, and reduced serum phosphate levels. Similarly, 1,25(OH)2D reduced furin activity, decreased iFGF23 cleavage, and increased total FGF23. In a post hoc analysis of a randomized clinical trial, we found that ergocalciferol treatment, which increased serum 1,25(OH)2D, significantly decreased serum furin activity and iFGF23 cleavage, compared with placebo. Thus, 1,25(OH)2D inhibits iFGF23 cleavage via VDR-mediated suppression of Furin expression, thereby providing a mechanism by which vitamin D can augment phosphaturic iFGF23 levels.
Han Xie, Isinsu Bastepe, Wen Zhou, Birol Ay, Zara Ceraj, Ignacio A. Portales-Castillo, Eva S. Liu, Sherri-Ann M. Burnett-Bowie, Harald Jüppner, Eugene P. Rhee, Murat Bastepe, Petra Simic
Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell–enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non–β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.
Jeeyeon Cha, Xin Tong, Emily M. Walker, Tehila Dahan, Veronica A. Cochrane, Sudipta Ashe, Ronan Russell, Anna B. Osipovich, Alex M. Mawla, Min Guo, Jin-hua Liu, Zachary A. Loyd, Mark O. Huising, Mark A. Magnuson, Matthias Hebrok, Yuval Dor, Roland Stein
X-linked hypophosphatemia (XLH) is characterized by high serum fibroblast growth factor 23 (FGF23) levels, resulting in impaired 1,25 dihydroxyvitamin D (1,25D) production. Adults with XLH develop a painful mineralization of the tendon-bone attachment site (enthesis), called enthesopathy. Treatment of mice with XLH (Hyp) with 1,25D or an anti-FGF23 antibody, both of which increase 1,25D signaling, prevents enthesopathy. Therefore, we undertook studies to determine a role for impaired 1,25D action in enthesopathy development. Entheses from mice lacking vitamin D 1-alpha-hydroxylase (Cyp27b1) (C-/-) had a similar enthesopathy to Hyp mice, while deletion of Fgf23 in Hyp mice prevented enthesopathy and deletion of both Cyp27b1 and Fgf23 in mice resulted in enthesopathy, demonstrating that the impaired 1,25D action due to high FGF23 levels underlied XLH enthesopathy development. Like Hyp mice, enthesopathy in C-/- mice was observed by P14 and was prevented, but not reversed, with 1,25D therapy. Deletion of the vitamin D receptor in scleraxis-expressing cells resulted in enthesopathy, indicating 1,25D acted directly on enthesis cells to regulate enthesopathy development. These results showed that 1,25D signaling was necessary for normal post-natal enthesis maturation and played a role in XLH enthesopathy development. Optimizing 1,25D replacement in pediatric XLH patients is necessary to prevent enthesopathy.
Rakshya Rana, Jiana T. Baker, Melissa Sorsby, Supriya Jagga, Shreya Venkat, Shaza Almardini, Eva S. Liu
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