Abstract：
OBJECTIVES:Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. METHODS:To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4). RESULTS:Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance. CONCLUSIONS:These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism.
journal_name
Mol Metabjournal_title
Molecular metabolismauthors
Langlet F,Tarbier M,Haeusler RA,Camastra S,Ferrannini E,Friedländer MR,Accili Ddoi
10.1016/j.molmet.2018.08.003subject
Has Abstractpub_date
2018-11-01 00:00:00pages
49-60issn
2212-8778pii
S2212-8778(18)30754-3journal_volume
17pub_type
杂志文章abstract：OBJECTIVE:Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates metabolic homeostasis. Previous work has suggested that impairment of FGF21 signaling in adipose tissue may occur through downregulation of the obligate FGF21 co-receptor, β-klotho, which leads to "FGF21 resistance" during the onset of...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2017.03.009
更新日期：2017-03-27 00:00:00
abstract：OBJECTIVE:Heart disease risk can be programmed by intrauterine exposure to obesity. Dysregulating key transcription factors in cardiac progenitors can cause subsequent adult-onset heart disease. In this study, we investigated the transcriptional pathways that are altered in the embryonic heart and linked to heart disea...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2020.101116
更新日期：2021-01-01 00:00:00
abstract：OBJECTIVE:Circulating long-chain free fatty acids (FFAs) are important metabolic signals that acutely enhance fatty acid oxidation, thermogenesis, energy expenditure, and insulin secretion. However, if chronically elevated, they provoke inflammation, insulin resistance, and β-cell failure. Moreover, FFAs act via multip...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2016.02.001
更新日期：2016-02-13 00:00:00
abstract：:Cytokine signaling has been connected to regulation of metabolism and energy balance. Numerous cytokine gene expression changes are stimulated by accumulation of bile acids in livers of young Foxa2 liver-conditional null mice. We hypothesized that bile acid-induced inflammation in young Foxa2 mutants, once chronic, af...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2013.08.005
更新日期：2013-08-24 00:00:00
abstract：BACKGROUND:The alarming rise of obesity and its associated comorbidities represents a medical burden and a major global health and economic issue. Understanding etiological mechanisms underpinning susceptibility and therapeutic response is of primary importance. Obesity, diabetes, and metabolic diseases are complex tra...
journal_title：Molecular metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.molmet.2018.05.010
更新日期：2018-08-01 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：BACKGROUND:Evidence hints at the ability of β-cells to emerge from non-β-cells upon genetic or pharmacological interventions. However, their quantitative contributions to the process of autonomous β-cell regeneration without genetic or pharmacological manipulations remain to be determined. METHODS & RESULTS:Using PANI...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2016.05.001
更新日期：2016-05-10 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：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：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：:The contribution of mitochondrial dysfunction to insulin resistance is a contentious issue in metabolic research. Recent evidence implicates mitochondrial dysfunction as contributing to multiple forms of insulin resistance. However, some models of mitochondrial dysfunction fail to induce insulin resistance, suggesting...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2014.02.001
更新日期：2014-03-12 00:00:00
abstract：OBJECTIVES:IL-13 is a cytokine classically produced by anti-inflammatory T-helper-2 lymphocytes; it is decreased in the circulation of type 2 diabetic patients and impacts positively on liver and skeletal muscle. Although IL-13 can exert positive effects on beta-cell lines, its impact and mode of action on primary beta...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2015.11.003
更新日期：2015-11-17 00:00:00
abstract：OBJECTIVE:Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mi...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2018.01.019
更新日期：2018-04-01 00:00:00
abstract：:Obesity is characterized as an excess accumulation of body fat resulting from a positive energy balance. It is the major risk factor for type 2 diabetes (T2D). The evidence for familial aggregation of obesity and its associated metabolic diseases is substantial. To date, about 150 genetic loci identified in genome-wid...
journal_title：Molecular metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.molmet.2013.09.002
更新日期：2013-09-25 00:00:00
abstract：OBJECTIVE:N-acylethanolamines play different roles in energy balance; anandamide (AEA) stimulates energy intake and storage, N-palmitoylethanolamide (PEA) counters inflammation, and N-oleoylethanolamide (OEA) mediates anorectic signals and lipid oxidation. Inconsistencies in the association of plasma N-acylethanolamine...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2018.06.002
更新日期：2018-08-01 00:00:00
abstract：OBJECTIVE/METHODS:DNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2016.11.003
更新日期：2016-11-16 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:In the adult brain, neural stem cells (NSCs) located in the subventricular zone (SVZ) produce both neuronal and glial cells. Thyroid hormones (THs) regulate adult NSC differentiation towards a neuronal phenotype, but also have major roles in mitochondrial metabolism. As NSC metabolism relies mainly on glycoly...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2017.08.003
更新日期：2017-11-01 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：BACKGROUND:Plasma insulin levels are predominantly the product of the morphological mass of insulin producing beta cells in the pancreatic islets of Langerhans and the functional status of each of these beta cells. Thus, deficiency in either beta cell mass or function, or both, can lead to insufficient levels of insuli...
journal_title：Molecular metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.molmet.2017.06.019
更新日期：2017-07-08 00:00:00
abstract：OBJECTIVE:During pregnancy, women normally increase their food intake and body fat mass, and exhibit insulin resistance. However, an increasing number of women are developing metabolic imbalances during pregnancy, including excessive gestational weight gain and gestational diabetes mellitus. Despite the negative health...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2014.12.005
更新日期：2014-12-19 00:00:00
abstract：OBJECTIVE:Obesity is an enormous burden for patients and health systems world-wide. Brown adipose tissue dissipates energy in response to cold and has been shown to be metabolically active in human adults. The type I transforming growth factor β (TGFβ) receptor Activin receptor-like kinase 7 (Alk7) is highly expressed ...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2015.06.003
更新日期：2015-06-14 00:00:00
abstract：:The lipin protein family of phosphatidate phosphatases has an established role in triacylglycerol synthesis and storage. Physiological roles for lipin-1 and lipin-2 have been identified, but the role of lipin-3 has remained mysterious. Using lipin single- and double-knockout models we identified a cooperative relation...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2013.11.008
更新日期：2013-11-28 00:00:00
abstract：OBJECTIVE:Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate en...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2018.03.008
更新日期：2018-05-01 00:00:00
abstract：OBJECTIVES:The skin is the largest sensory organ of the human body and plays a fundamental role in regulating body temperature. However, adaptive alterations in skin functions and morphology have only vaguely been associated with physiological responses to cold stress or sensation of ambient temperatures. We previously...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2020.101144
更新日期：2020-12-18 00:00:00
abstract：OBJECTIVE:Surplus dietary fat cannot be converted into other macronutrient forms or excreted, so has to be stored or oxidized. Healthy mammals store excess energy in the form of triacylgycerol (TAG) in lipid droplets within adipocytes rather than oxidizing it, and thus ultimately gain weight. The 'overflow hypothesis' ...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2018.05.006
更新日期：2018-07-01 00:00:00
abstract：OBJECTIVE AND METHODS:Metabolic viscera and their vasculature are richly innervated by peripheral sensory neurons. Here, we examined the metabolic and inflammatory profiles of mice with selective ablation of all Nav1.8-expressing primary afferent neurons. RESULTS:While mice lacking sensory neurons displayed no differe...
journal_title：Molecular metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.molmet.2017.07.012
更新日期：2017-10-01 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:Aging and weight gain lead to a decline in brown and beige adipocyte functionality that exacerbates obesity and insulin resistance. We sought to determine whether sphingolipids, such as ceramides, a class of lipid metabolites that accumulate in aging and overnutrition, are sufficient or necessary for the meta...
journal_title：Molecular metabolism
pub_type： 杂志文章
doi：10.1016/j.molmet.2020.101145
更新日期：2020-12-19 00:00:00
