Sympathetic Overdrive and Unrestrained Adipose Lipolysis Drive Alcohol-Induced Hepatic Steatosis in Rodents

AUTHORS

Chunxue Zhou 1, Henry H. Ruiz, Li Ling, Giulia Maurizi, Kenichi Sakamoto, Claudia Liberini, Ling Wang, Adrien Stanley, Hale E. Egritag, Sofia M. Sanz, Claudia Lindtner, Mary A. Butera, Christoph Buettner

ABSTRACT

Objective

Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain-SNS-adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver.

Methods

We examined the role of lipolysis, and the brain-SNS-adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress.

Results

Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis.

Conclusions

Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

AUTHORS

Lindsey H. Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V. Nayak, Paulo El Parente, Margaux Sambon, Pablo J. Atria, Mohamed A. E. Ali, Lukasz Witek, Alesha B. Castillo, Christopher Y, Park, Ralf H. Adams, Aristotelis Tsirigos, Sophie M. Morgani & Philipp Leucht

ABSTRACT

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Histological Compatibility in Distal Neurotizations: A Systematic Review

AUTHORS

Cristina Schmitt Cavalheiro, João Carlos Nakamoto, Teng Hsiang Wei, Luiz Sorrenti, Erick Yoshio Wataya

ABSTRACT

Considering the importance of defining the minimum number of axons between recipient and donor branches, that is, the definition of histological compatibility in distal neurotizations for the success of the procedure and the surgeon's freedom to choose individualized strategies for each patient, this systematic review was conducted to find out the most recent studies on the subject. The objective of this systematic review was to determine the importance of the number of axons and the relationship between axon counts in the donor and recipient nerves in the success of nerve transfer. A literature review was performed on five international databases: Web of Science, Scopus, Wiley (Cochrane Database), Embase, and PubMed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed (2020 version), a guide designed to guide the elaboration of systematic literature reviews. One hundred and fifty-seven studies were found, and 23 were selected based on the eligibility criteria. The articles presented were conclusive in determining the importance of the number of axons in the success of nerve transfer. Still, the relationship between the number of axons in the donor and recipient nerves seems more relevant in the success of transfers and is not always explored by the authors. The review of the articles has provided compelling evidence that the number of axons is a critical determinant of the success of nerve transfer procedures. However, the relationship between the number of axons in the donor nerve and that in the recipient nerve appears to be even more crucial for successful transfers, a factor that is not always adequately explored by authors in the existing literature.

BAP1 promotes osteoclast function by metabolic reprogramming

AUTHORS

Nidhi Rohatgi, Wei Zou, Yongjia Li, Kevin Cho, Patrick L. Collins, Eric Tycksen, Gaurav Pandey, Carl J. DeSelm, Gary J. Patti, Anwesha Dey & Steven L. Teitelbaum

ABSTRACT

Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1∆LysM), arrests osteoclast function but not formation. Bap1∆LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.

Local BMP2 hydrogel therapy for robust bone regeneration in a porcine model of Legg-Calvé-Perthes disease

AUTHORS

Chi Ma, Min Sung Park, Felipe Alves do Monte, Vishal Gokani, Olumide O. Aruwajoye, Yinshi Ren, Xiaohua Liu & Harry K. W. Kim

ABSTRACT

Legg-Calvé-Perthes disease is juvenile idiopathic osteonecrosis of the femoral head (ONFH) that has no effective clinical treatment. Previously, local injection of bone morphogenetic protein-2 (BMP2) for ONFH treatment showed a heterogeneous bone repair and a high incidence of heterotopic ossification (HO) due to the BMP2 leakage. Here, we developed a BMP2-hydrogel treatment via a transphyseal bone wash and subsequential injection of BMP2-loaded hydrogel. In vitro studies showed that a hydrogel of gelatin-heparin-tyramine retained the BMP2 for four weeks. The injection of the hydrogel can efficiently prevent leakage. With the bone wash, the injected hydrogel had a broad distribution in the head. In vivo studies on pigs revealed that the BMP2-hydrogel treatment produced a homogeneous bone regeneration without HO. It preserved the subchondral contour and restored the subchondral endochondral ossification, although it increased growth plate fusions. In summary, the study demonstrated a promising BMP2-hydrogel treatment for ONFH treatment, especially for teenagers.

Multi-organ phenotypes in mice lacking latent TGFβ binding protein 2 (LTBP2)

AUTHORS

Nicholas K. Bodmer, Russell H. Knutsen, Robyn A. Roth, Ryan M. Castile, Michael D. Brodt, Carrie M. Gierasch, Thomas J. Broekelmann, Mark A. Gibson, Jeffrey A. Haspel, Spencer P. Lake, Jeffrey R. Koenitzer, Steven L. Brody, Matthew J. Silva, Robert P. Mecham, David M. Ornitz

ABSTRACT

Background

Latent TGFβ binding protein-2 (LTBP2) is a fibrillin 1 binding component of the microfibril. LTBP2 is the only LTBP protein that does not bind any isoforms of TGFβ, although it may interfere with the function of other LTBPs or interact with other signaling pathways.

Results

Here, we investigate mice lacking Ltbp2 (Ltbp2−/−) and identify multiple phenotypes that impact bodyweight and fat mass, and affect bone and skin development. The alterations in skin and bone development are particularly noteworthy since the strength of these tissues is differentially affected by loss of Ltbp2. Interestingly, some tissues that express high levels of Ltbp2, such as the aorta and lung, do not have a developmental or homeostatic phenotype.

Conclusions

Analysis of these mice show that LTBP2 has complex effects on development through direct effects on the extracellular matrix (ECM) or on signaling pathways that are known to regulate the ECM.