News Roundup

Abolished InsP₃R2 function inhibits sweat secretion in both humans and mice

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Abstract

There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweating is a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat (anhidrosis) results in heat intolerance that may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineous family with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5-trisphosphate receptor (InsP₃R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP₃R2 and abrogates Ca²⁺ release from the endoplasmic reticulum, which suggests that intracellular Ca²⁺ release by InsP₃R2 in clear cells of the sweat glands is important for eccrine sweat production. Itpr2^–/– mice exhibited a marked reduction in sweat secretion, and evaluation of sweat glands from Itpr2^–/– animals revealed a decrease in Ca²⁺ response compared with controls. Together, our data indicate that loss of InsP₃R2-mediated Ca²⁺ release causes isolated anhidrosis in humans and suggest that specific InsP₃R inhibitors have the potential to reduce sweat production in hyperhidrosis.

Authors

Joakim Klar, Chihiro Hisatsune, Shahid M. Baig, Muhammad Tariq, Anna C.V. Johansson, Mahmood Rasool, Naveed Altaf Malik, Adam Ameur, Kotomi Sugiura, Lars Feuk, Katsuhiko Mikoshiba, Niklas Dahl

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

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Abstract

The bile acid–responsive G protein–coupled receptor TGR5 is involved in several metabolic processes, and recent studies suggest that TGR5 activation may promote pathways that are protective against diet-induced diabetes. Here, we investigated the role of macrophage-specific TGR5 signaling in protecting adipose tissue from inflammation and associated insulin resistance. Examination of adipose tissue from obese mice lacking macrophage Tgr5 revealed enhanced inflammation, increased chemokine expression, and higher macrophage numbers compared with control obese animals. Moreover, macrophage-specific deletion of Tgr5 exacerbated insulin resistance in obese animals. Conversely, pharmacological activation of TGR5 markedly decreased LPS-induced chemokine expression in primary macrophages. This reduction was mediated by AKT-dependent activation of mTOR complex 1, which in turn induced the differential translation of the dominant-negative C/EBPβ isoform, liver inhibitory protein (LIP). Overall, these studies reveal a signaling pathway downstream of TGR5 that modulates chemokine expression in response to high-fat diet and suggest that targeting this pathway has the potential to be therapeutically exploited for prevention of chronic inflammatory diseases and type 2 diabetes mellitus.

Authors

Alessia Perino, Thijs Willem Hendrik Pols, Mitsunori Nomura, Sokrates Stein, Roberto Pellicciari, Kristina Schoonjans

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

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Abstract

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.

Authors

David G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, Peter A. Crawford

Hair keratin mutations in tooth enamel increase dental decay risk

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Abstract

Tooth enamel is the hardest substance in the human body and has a unique combination of hardness and fracture toughness that protects teeth from dental caries, the most common chronic disease worldwide. In addition to a high mineral content, tooth enamel comprises organic material that is important for mechanical performance and influences the initiation and progression of caries; however, the protein composition of tooth enamel has not been fully characterized. Here, we determined that epithelial hair keratins, which are crucial for maintaining the integrity of the sheaths that support the hair shaft, are expressed in the enamel organ and are essential organic components of mature enamel. Using genetic and intraoral examination data from 386 children and 706 adults, we found that individuals harboring known hair disorder–associated polymorphisms in the gene encoding keratin 75 (KRT75), KRT75^A161T and KRT75^E337K, are prone to increased dental caries. Analysis of teeth from individuals carrying the KRT75^A161T variant revealed an altered enamel structure and a marked reduction of enamel hardness, suggesting that a functional keratin network is required for the mechanical stability of tooth enamel. Taken together, our results identify a genetic locus that influences enamel structure and establish a connection between hair disorders and susceptibility to dental caries.

Authors

Olivier Duverger, Takahiro Ohara, John R. Shaffer, Danielle Donahue, Patricia Zerfas, Andrew Dullnig, Christopher Crecelius, Elia Beniash, Mary L. Marazita, Maria I. Morasso

Sustained increase in α5GABA_A receptor function impairs memory after anesthesia

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Abstract

Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months. The mechanisms underlying this postoperative cognitive dysfunction in the adult brain remain poorly understood. Depression of brain function during anesthesia is attributed primarily to increased activity of γ-aminobutyric acid type A receptors (GABA_ARs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABA_ARs rapidly returns to baseline and these receptors no longer impair memory. Here, using a murine model, we found that a single in vivo treatment with the injectable anesthetic etomidate increased a tonic inhibitory current generated by α5 subunit–containing GABA_ARs (α5GABA_ARs) and cell-surface expression of α5GABA_ARs for at least 1 week. The sustained increase in α5GABA_AR activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABA_ARs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of α5GABA_ARs. Thus, α5GABA_AR function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.

Authors

Agnieszka A. Zurek, Jieying Yu, Dian-Shi Wang, Sean C. Haffey, Erica M. Bridgwater, Antonello Penna, Irene Lecker, Gang Lei, Tom Chang, Eric W.R. Salter, Beverley A. Orser