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Journal ArticleDOI: 10.1016/J.CMET.2021.01.012

Metabolic stress drives sympathetic neuropathy within the liver.

02 Mar 2021-Cell Metabolism (Elsevier BV)-Vol. 33, Iss: 3
Abstract: The nervous system instructs the body's metabolism, including that in the liver. However, the neural anatomy of the liver under either normal or metabolically stressed conditions remains to be unequivocally assessed. Here, we examined neural distributions in the mouse, nonhuman primate, and human livers with advanced 3D imaging. We observed that neural innervations within the liver are predominantly sympathetic, but not parasympathetic, inputs. Moreover, we discovered the profound and reversible loss of such sympathetic innervations during metabolic challenges. This hepatic sympathetic neuropathy was caused by TNFα derived from CD11b+ F4/80+ immune cells under high-fat-diet (HFD) condition. We further demonstrated that the Sarm1 deletion mitigated the hepatic sympathetic neuropathy and improved metabolic parameters in HFD-challenged mice. Mechanistically, the sympathetic neurotransmitter norepinephrine attenuated the immune-cell inflammation that would otherwise trigger the insulin insensitivity of hepatocytes. These results together reveal the previously unrecognized neuropathic event in the liver with metabolic relevance.

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Topics: Norepinephrine (54%), Nervous system (53%)
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7 results found


Open accessJournal ArticleDOI: 10.3389/FMOLB.2021.703532
Abstract: Axon degeneration represents a pathological feature of many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease where axons die before the neuronal soma, and axonopathies, such as Charcot-Marie-Tooth disease and hereditary spastic paraplegia. Over the last two decades, it has slowly emerged that a central signaling pathway forms the basis of this process in many circumstances. This is an axonal NAD-related signaling mechanism mainly regulated by the two key proteins with opposing roles: the NAD-synthesizing enzyme NMNAT2, and SARM1, a protein with NADase and related activities. The crosstalk between the axon survival factor NMNAT2 and pro-degenerative factor SARM1 has been extensively characterized and plays an essential role in maintaining the axon integrity. This pathway can be activated in necroptosis and in genetic, toxic or metabolic disorders, physical injury and neuroinflammation, all leading to axon pathology. SARM1 is also known to be involved in regulating innate immunity, potentially linking axon degeneration to the response to pathogens and intercellular signaling. Understanding this NAD-related signaling mechanism enhances our understanding of the process of axon degeneration and enables a path to the development of drugs for a wide range of neurodegenerative diseases.

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Topics: Axon (57.99%), Necroptosis (52%), Neuroinflammation (50%)

3 Citations


Journal ArticleDOI: 10.1038/S41568-021-00382-W
Abstract: The visualization of whole organs and organisms through tissue clearing and fluorescence volumetric imaging has revolutionized the way we look at biological samples. Its application to solid tumours is changing our perception of tumour architecture, revealing signalling networks and cell interactions critical in tumour progression, and provides a powerful new strategy for cancer diagnostics. This Review introduces the latest advances in tissue clearing and three-dimensional imaging, examines the challenges in clearing epithelia — the tissue of origin of most malignancies — and discusses the insights that tissue clearing has brought to cancer research, as well as the prospective applications to experimental and clinical oncology. This Review introduces the latest advances in tissue clearing and three-dimensional imaging as applied to epithelial tissues, and explains how such techniques can improve both our understanding of tumour biology and cancer diagnostics.

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1 Citations


Open accessJournal ArticleDOI: 10.1126/SCIADV.ABG5733
Csaba Adori1, Teresa Daraio1, Raoul Kuiper1, Swapnali Barde1  +21 moreInstitutions (8)
01 Jul 2021-Science Advances
Abstract: Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.

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Topics: Steatohepatitis (61%), Nonalcoholic fatty liver disease (56.99%), Portal hypertension (52%) ... show more

Journal ArticleDOI: 10.2337/DB20-1030
Jianbo Xiu1, Rongrong Han1, Zeyue Liu1, Jiayu Li1  +4 moreInstitutions (2)
07 May 2021-Diabetes
Abstract: Moods and metabolism modulate each other. High comorbidity of depression and metabolic disorders, such as diabetes and obesity, poses a great challenge to treat such conditions. Here we report the therapeutic efficacy of brain-derived neurotrophic factor (BDNF) by gene transfer in the dorsal raphe nucleus (DRN) in a chronic unpredictable mild stress model (CUMS) of depression and models of diabetes and obesity. In CUMS, BDNF-expressing mice displayed antidepressant- and anxiolytic-like behaviors, which are associated with augmented serotonergic activity. Both in the diet-induced obesity model (DIO) and in db/db mice, BDNF ameliorated obesity and diabetes, which may be mediated by enhanced sympathetic activity not involving DRN serotonin. Chronic activation of DRN neurons via chemogenetic tools produced similar effects as BDNF in DIO mice. These results established the DRN as a key nexus in regulating depression-like behaviors and metabolism, which can be exploited to combat comorbid depression and metabolic disorders via BDNF gene transfer.

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Topics: Dorsal raphe nucleus (53%), Serotonergic (52%), Antidepressant (50%)

Journal ArticleDOI: 10.1002/HEP.32055
15 Aug 2021-Hepatology
Abstract: The liver is innervated by autonomic and sensory fibers of the sympathetic and parasympathetic nervous systems that regulate liver function, regeneration, and disease. Although the importance of the hepatic nervous system in maintaining and restoring liver homeostasis is increasingly appreciated, much remains unknown about the specific mechanisms by which hepatic nerves both influence and are influenced by liver diseases. While recent work has begun to illuminate the developmental mechanisms underlying recruitment of nerves to the liver, evolutionary differences contributing to species-specific patterns of hepatic innervation remain elusive. In this review, we summarize current knowledge on the development of the hepatic nervous system and its role in liver regeneration and disease. We also highlight areas in which further investigation would greatly enhance our understanding of the evolution and function of liver innervation.

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Topics: Liver function (66%), Liver regeneration (56.99%), Nervous system (56.99%) ... show more

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57 results found


Journal ArticleDOI: 10.1038/NM.2627
Olivia Osborn1, Jerrold M. Olefsky1Institutions (1)
01 Mar 2012-Nature Medicine
Abstract: It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver

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Topics: Disease (50%)

1,188 Citations


Open accessOtherDOI: 10.1002/CPHY.C130024
Liangyou Rui1Institutions (1)
Abstract: The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases.

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Topics: Starvation response (66%), Lipogenesis (65%), Ketone bodies (64%) ... show more

1,018 Citations


Open accessJournal ArticleDOI: 10.1038/NRI2449
Gökhan S. Hotamisligil1, Ebru Erbay1Institutions (1)
Abstract: The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.

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873 Citations


Journal ArticleDOI: 10.1146/ANNUREV.NUTR.26.061505.111258
George F. Cahill1Institutions (1)
Abstract: ■ Abstract This article, which is partly biographical and partly scientific, summarizes a life in academic medicine. It relates my progress from benchside to bedside and then to academic and research administration, and concludes with the teaching of human biology to college undergraduates. My experience as an intern (anno 1953) treating a youngster in diabetic ketoacidosis underscored our ignorance of the controls in human fuel metabolism. Circulating free fatty acids were then unknown, insulin could not be measured in biologic fluids, and β-hydroxybutyric acid, which was difficult to measure, was considered by many a metabolic poison. The central role of insulin and the metabolism of free fatty acids, glycerol, glucose, lactate, and pyruvate, combined with indirect calorimetry, needed characterization in a near-steady state, namely prolonged starvation. This is the main topic of this chapter. Due to its use by brain, D-β-hydroxybutyric acid not only has permitted man to survive prolonged starvation, but also may have therapeutic potential owing to its greater efficiency in providing cellular energy in ischemic states such as stroke, myocardial insufficiency, neonatal stress, genetic mitochondrial problems, and physical fatigue.

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Topics: Starvation (52%)

768 Citations


Open accessJournal ArticleDOI: 10.1046/J.1365-2796.1999.00490.X
G. S. Hotamisligil1Institutions (1)
Abstract: Insulin resistance, a smaller than expected response to a given dose of insulin, is associated with many common diseases including, ageing, polycystic ovarian disease, syndrome X, cancer, infections, trauma and, most significantly, obesity and type 2 diabetes mellitus. The biochemical basis of insulin resistance in type 2 diabetes has been the subject of many studies. Earlier studies have indicated that quantitative regulation of the insulin sensitive glucose transporters (Glut-4) and insulin receptors themselves may contribute to this disorder, however, these two factors are probably inadequate to explain the extent of insulin resistance. This point also became apparent by the development of only mild hyperinsulinaemia in mice with a targeted mutation in the Glut-4 gene. Studies on postreceptor defects in type 2 diabetes has recently focused on the intrinsic catalytic activity of the insulin receptor and downstream signalling events. A reduction in tyrosine phosphorylation of both the insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1) has been noted in both animal and human type 2 diabetes. Importantly, this appears to occur in all of the major insulin-sensitive tissues, namely the muscle, fat and liver. It is now clear that decreased signalling capacity of the insulin receptor is an important component of this disease. I will review some of the potential mechanisms underlying this deficiency.

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Topics: Insulin resistance (74%), Insulin receptor (74%), Insulin (69%) ... show more

739 Citations


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20217