Abstract:
OBJECTIVE:The glycoprotein hormone erythropoietin (EPO) is required for erythropoiesis, and the kidney is the primary site of adult EPO synthesis. Limited evidence has suggested that EPO could be detectable in the brain under certain conditions, but it remains unknown if the brain might have its own EPO system for biological functions that are independent of peripheral EPO production and action. We performed this study to address this question using mice under normal conditions versus pathophysiological conditions including aging and dietary obesity. METHODS:EPO expression was measured in different brain regions as well as in the cerebrospinal fluid. Hypothalamic ventricular EPO was administered to physiologically examine possible therapeutic effects on the conditions of aging and dietary obesity. Body weight, body composition, insulin tolerance, and glucose tolerance were measured to assess the central effects of EPO on metabolic physiology, and muscle strength and histology were analyzed to assess the central effects of EPO on muscle function. In addition, β2-adrenergic receptor knockout bone marrow transplant was employed to determine the potential role of bone marrow in linking the brain to some of these peripheral functions. RESULTS:This study revealed that EPO is expressed in the ventromedial hypothalamus in addition to a few other brain regions and is present in the cerebrospinal fluid. Unlike blood EPO concentration, which increased with aging and dietary obesity, hypothalamic EPO decreased in these disease conditions. Therapeutically, aged mice were chronically treated with EPO in the hypothalamic ventricle, showing an increase in lean mass, while body weight and fat mass decreased as a result of a moderate reduction of food intake. Both muscle and metabolic functions were improved by this central treatment, and mechanistically, adrenergic signals to the bone marrow played a role in conveying hypothalamic EPO to these peripheral actions. Dietary obesity was also studied, showing that hypothalamic EPO treatment caused a reduction in food intake and obesity, leading to improved metabolic functions related to decreased fat as well as increased lean mass. CONCLUSIONS:Hypothalamic EPO plays a role in the central regulation of muscle and metabolic physiology, while its decline contributes to aging and obesity physiology in a manner that is independent of peripheral EPO.
journal_name
Mol Metabjournal_title
Molecular metabolismauthors
Wang Z,Khor S,Cai Ddoi
10.1016/j.molmet.2019.12.001subject
Has Abstractpub_date
2020-02-01 00:00:00pages
56-68issn
2212-8778pii
S2212-8778(19)30952-4journal_volume
32pub_type
杂志文章abstract:OBJECTIVE:Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current stud...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.12.004
更新日期:2019-02-01 00:00:00
abstract:OBJECTIVE:α/β-Hydrolase domain-6 (ABHD6) is a newly identified monoacylglycerol (MAG) lipase. We recently reported that it negatively regulates glucose stimulated insulin secretion (GSIS) in the β cells by hydrolyzing lipolysis-derived MAG that acts as a metabolic coupling factor and signaling molecule via exocytotic r...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2015.09.012
更新日期:2015-10-08 00:00:00
abstract:OBJECTIVE:Identification of additional regulatory factors involved in the onset of obesity is important to understand the mechanisms underlying this prevailing disease and its associated metabolic disorders and to develop therapeutic strategies. Through isolation and analysis of a mutant, we aimed to uncover the functi...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2017.03.003
更新日期:2017-03-18 00:00:00
abstract:OBJECTIVE:Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. METHODS:We employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. W...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2020.101057
更新日期:2020-12-01 00:00:00
abstract::Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expo...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2014.03.007
更新日期:2014-04-02 00:00:00
abstract:OBJECTIVE:Understanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.05.004
更新日期:2019-07-01 00:00:00
abstract::Genetic variation in FFAR1 modulates insulin secretion dependent on non-esterified fatty acid (NEFA) concentrations. We previously demonstrated lower insulin secretion in minor allele carriers of PPARG Pro12Ala in high-NEFA environment, but the mode of action could not been revealed. We tested if this effect is mediat...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2014.07.001
更新日期:2014-07-07 00:00:00
abstract:OBJECTIVE:Metabolic challenges, such as a cold environment, stimulate sympathetic neural efferent activity to white adipose tissue (WAT) to drive lipolysis, thereby increasing the availability of free fatty acids as one source of fuel for brown adipose tissue (BAT) thermogenesis. WAT is also innervated by sensory nerve...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2016.06.013
更新日期:2016-06-30 00:00:00
abstract:OBJECTIVE:GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets are limited to regulating insulin secretion. The current study expands research on its action. METHODS AND RESULTS:We demonstra...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.02.008
更新日期:2018-05-01 00:00:00
abstract:OBJECTIVE:Introduction of a high-fat diet to mice results in a period of voracious feeding, known as hyperphagia, before homeostatic mechanisms prevail to restore energy intake to an isocaloric level. Acute high-fat diet hyperphagia induces astrocyte activation in the rodent hypothalamus, suggesting a potential role of...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2014.10.001
更新日期:2014-10-16 00:00:00
abstract:OBJECTIVES:Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) regulate food intake and body weight, glucose metabolism and convey the reward value of sucrose. In this report, we set out to establish the respective roles of MCH and conventional neurotransmitters in these neurons. METHODS:MCH n...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.05.001
更新日期:2018-07-01 00:00:00
abstract:OBJECTIVE:Pharmacological activation of adenosine signaling has been shown to increase β-cell proliferation and thereby β-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating β-cell proliferation is unknown. The objective of this study was to dete...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2016.09.006
更新日期:2016-09-20 00:00:00
abstract:OBJECTIVES:Hepatokines are proteins secreted by the liver that impact the functions of the liver and various tissues through autocrine, paracrine, and endocrine signaling. Recently, Tsukushi (TSK) was identified as a new hepatokine that is induced by obesity and cold exposure. It was proposed that TSK controls sympathe...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.09.014
更新日期:2019-12-01 00:00:00
abstract:OBJECTIVE:The enteroendocrine hormone glucagon-like peptide 1 (GLP-1) is an attractive anti-diabetic therapy. Here, we generated a recombinant Lactococcus lactis strain genetically modified to produce GLP-1 and investigated its ability to improve glucose tolerance in mice on chow or high-fat diet (HFD). METHODS:We tra...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2016.06.006
更新日期:2016-06-22 00:00:00
abstract:OBJECTIVE:Mice with congenital loss of the glucagon receptor gene (Gcgr-/- mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that inc...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.07.012
更新日期:2018-11-01 00:00:00
abstract::Decreased β-cell mass reflects a shift from quiescence/proliferation into apoptosis, it plays a crucial role in the pathophysiology of diabetes. A major attempt to restore β-cell mass and normoglycemia is to improve β-cell survival. Here we show that switching off the Fas pathway using Fas apoptotic inhibitory protein...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2012.08.006
更新日期:2012-08-17 00:00:00
abstract:BACKGROUND:While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in hum...
journal_title:Molecular metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.molmet.2015.12.006
更新日期:2016-01-14 00:00:00
abstract:OBJECTIVE:Increasing adaptive thermogenesis by stimulating browning in white adipose tissue is a promising method of improving metabolic health. However, the molecular mechanisms underlying this transition remain elusive. Our study examined the molecular determinants driving the differentiation of precursor cells into ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2020.101137
更新日期:2020-12-05 00:00:00
abstract:OBJECTIVE:Fasting results in major metabolic changes including a switch from glycogenolysis to gluconeogenesis to maintain glucose homeostasis. However, the relationship between the length of fasting and the relative contribution of gluconeogenic substrates remains unclear. We investigated the relative contribution of ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.11.005
更新日期:2020-01-01 00:00:00
abstract:BACKGROUND/OBJECTIVES:Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior. METHODS:To investigate the function of Pp...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2015.04.005
更新日期:2015-05-02 00:00:00
abstract:BACKGROUND:Poly-ADP-ribose polymerases (PARPs) are key mediators of cellular stress response. They are intimately linked to cellular metabolism through the consumption of NAD+. PARP1/ARTD1 in the nucleus is the major NAD+ consuming activity and plays a key role in maintaining genomic integrity. SCOPE OF REVIEW:In this...
journal_title:Molecular metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.molmet.2020.01.014
更新日期:2020-08-01 00:00:00
abstract:OBJECTIVE:Changes to the microbial community in the human gut have been proposed to promote metabolic disturbances that also occur after short periods of sleep loss (including insulin resistance). However, whether sleep loss affects the gut microbiota remains unknown. METHODS:In a randomized within-subject crossover s...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2016.10.003
更新日期:2016-10-24 00:00:00
abstract:OBJECTIVES:Preferential damage to fast, glycolytic myofibers is common in many muscle-wasting diseases, including Duchenne muscular dystrophy (DMD). Promoting an oxidative phenotype could protect muscles from damage and ameliorate the dystrophic pathology with therapeutic relevance, but developing efficacious strategie...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2020.101157
更新日期:2020-12-24 00:00:00
abstract:BACKGROUND:In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular t...
journal_title:Molecular metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.molmet.2018.05.009
更新日期:2018-09-01 00:00:00
abstract:OBJECTIVE:Studies using the estrogen receptor alpha (ERα) knock-out (αERKO) mice have demonstrated that ERα plays a crucial role in various estrogen-mediated metabolic regulations. ERα is a ligand dependent transcription regulator and its activity is regulated by estrogenic compounds. ERα consists of two transcriptiona...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.09.006
更新日期:2018-12-01 00:00:00
abstract:OBJECTIVE:Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play a paramount role in the central regulation of energy balance. Despite the substantial body of genetic evidence implicating BDNF- or TrkB-deficiency in human obesity, the critical brain region(s) contributing ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2015.08.002
更新日期:2015-08-18 00:00:00
abstract:OBJECTIVE:Leptin (Lep) plays a crucial role in controlling food intake and energy expenditure. Defective Lep/LepRb-signaling leads to fat accumulation, massive obesity, and the development of diabetes. We serendipitously noticed spontaneous development of obesity similar to LepR-deficient (db/db) mice in offspring from...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.04.010
更新日期:2019-07-01 00:00:00
abstract:OBJECTIVE:Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) an...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2017.12.005
更新日期:2018-02-01 00:00:00
abstract::Melanocortins and their receptors are critical components of energy homeostasis and the paraventricular nucleus of the hypothalamus (PVH) is an important site of melanocortin action. Although best known for its role in osmoregulation, arginine vasopressin (AVP) has been implicated in feeding and is robustly expressed ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2013.12.006
更新日期:2014-01-08 00:00:00
abstract::11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) plays a key role in glucocorticoid receptor (GR) activation. Besides, it metabolizes some oxysterols and bile acids (BAs). The GR regulates BA homeostasis; however, the impact of impaired 11β-HSD1 activity remained unknown. We profiled plasma and liver BAs in liver-specifi...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2014.04.008
更新日期:2014-05-02 00:00:00