Abstract:
OBJECTIVE:Despite the large body of work describing the tumor suppressor functions of Phosphatase and tensin homologue deleted on chromosome ten (PTEN), its roles in adipose homeostasis of adult animals are not yet fully understood. Here, we sought to determine the role of PTEN in whole-body adipose homeostasis. METHODS:We genetically manipulated PTEN in specific fat depots through recombinant adeno-associated viral vector (rAAV)-based gene transfer of Cre recombinase to adult PTENflox mice. Additionally, we used a denervation agent, 6OHDA, to assess the role of sympathetic signaling in PTEN-related adipose remodeling. Furthermore, we chemically manipulated AKT signaling via a pan-AKT inhibitor, MK-2206, to assess the role of AKT in PTEN-related adipose remodeling. Finally, to understand the role of leptin and central signaling on peripheral tissues, we knocked down hypothalamic leptin receptor with a microRNA delivered by a rAAV vector. RESULTS:Knockdown PTEN in individual fat depot resulted in massive expansion of the affected fat depot through activation of AKT signaling associated with suppression of lipolysis and induction of leptin. This hypertrophic expansion of the affected fat depot led to upregulation of PTEN level, higher lipolysis, and induction of white fat browning in other fat depots, and the compensatory reduced fat mass to maintain a set point of whole-body adiposity. Administration of AKT inhibitor MK-2206 prevented the adipose PTEN knockdown-associated effects. 6OHDA-mediated denervation demonstrated that sympathetic innervation was required for the PTEN knockdown-induced adipose redistribution. Knockdown hypothalamic leptin receptor attenuated the adipose redistribution induced by PTEN deficiency in individual fat depot. CONCLUSIONS:Our results demonstrate the essential role of PTEN in adipose homeostasis, including mass and distribution in adulthood, and reveal an "adipose PTEN-leptin-sympathetic nervous system" feedback loop to maintain a set point of adipose PTEN and whole-body adiposity.
journal_name
Mol Metabjournal_title
Molecular metabolismauthors
Huang W,Queen NJ,McMurphy TB,Ali S,Cao Ldoi
10.1016/j.molmet.2019.09.008subject
Has Abstractpub_date
2019-12-01 00:00:00pages
48-60issn
2212-8778pii
S2212-8778(19)30911-1journal_volume
30pub_type
杂志文章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:OBJECTIVE:Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the gut in response to nutrient ingestion and promotes meal-dependent insulin secretion and lipid metabolism. Loss or attenuation of GIP receptor (GIPR) action leads to resistance to diet-induced obesity through incompletely understood mechan...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.08.006
更新日期:2019-10-01 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
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::Metabolic endotoxemia triggers inflammation, targets cells from the stroma-vascular fraction of adipose depots, and metabolic disease. To identify these cells we here infused mice with lipopolysaccharides and showed by FACS analyses and BrdU staining that the number of small subcutaneous adipocytes, preadipocytes and ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2013.06.005
更新日期:2013-07-04 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:Functional investigation of novel gene/protein targets associated with adipocyte differentiation or function heavily relies on efficient and accessible tools to manipulate gene expression in adipocytes in vitro. Recent advances in gene-editing technologies such as CRISPR-Cas9 have not only eased gene editing ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2017.07.001
更新日期:2017-10-01 00:00:00
abstract:BACKGROUND:Recent changes in nutrition and lifestyle have provoked an unprecedented increase in the prevalence of obesity and metabolic disorders. Recognition of the adverse effects on health has prompted intense efforts to understand the molecular determinants of insulin sensitivity and dysglycemia. In many respects, ...
journal_title:Molecular metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.molmet.2018.10.008
更新日期:2019-01-01 00:00:00
abstract::Several lines of evidence suggest that novel pharmacological approaches aimed at converting white adipose tissue (WAT) into brown adipose tissue (BAT) may represent an effective therapeutic strategy for obesity and related disorders. ((18))F-fluorodeoxyglucose ((18)F-FDG) is the only positron emission tomography (PET)...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2013.04.002
更新日期:2013-04-21 00:00:00
abstract:OBJECTIVES:Nutrient sensing by hypothalamic neurons is critical for the regulation of food intake and energy expenditure. We aimed to identify long- and medium-chain fatty acid species transported into the brain, their effects on energy balance, and the mechanisms by which they regulate activity of hypothalamic neurons...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2020.01.002
更新日期:2020-04-01 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:BACKGROUND:Gut microbiota is considered as a major regulator of metabolic disease. This reconciles the notion of metabolic inflammation and the epidemic development of the disease. In addition to evidence showing that a specific gut microbiota characterizes patients with obesity, type 2 diabetes, and hepatic steatosis,...
journal_title:Molecular metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.molmet.2016.05.016
更新日期:2016-06-06 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:The C57Bl/6J (Bl/6J) mouse is the most widely used strain in metabolic research. This strain carries a mutation in nicotinamide nucleotide transhydrogenase (Nnt), a mitochondrial enzyme involved in NADPH production, which has been suggested to lead to glucose intolerance and beta-cell dysfunction. However, re...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2014.09.006
更新日期:2014-09-28 00:00:00
abstract:OBJECTIVE:Hypothalamic glucose sensing (HGS) initiates insulin secretion (IS) via a vagal control, participating in energy homeostasis. This requires mitochondrial reactive oxygen species (mROS) signaling, dependent on mitochondrial fission, as shown by invalidation of the hypothalamic DRP1 protein. Here, our objective...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.11.007
更新日期:2019-02-01 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:We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature. METHODS:The effect of environmental temperature (4-33 °C) on body temperature, energy expenditure, physical activity, and food intake in various mice (chow diet, high-fat diet, Brs3 (-/y) , lipodystrophic...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2015.03.001
更新日期:2015-03-10 00:00:00
abstract:BACKGROUND:The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. H...
journal_title:Molecular metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.molmet.2019.10.002
更新日期:2020-03-01 00:00:00
abstract:OBJECTIVE:The sympathetic nervous system (SNS) is a key regulator of the metabolic and endocrine functions of adipose tissue. Increased SNS outflow promotes fat mobilization, stimulates non-shivering thermogenesis, promotes browning, and inhibits leptin production. Most of these effects are attributed to norepinephrine...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.06.019
更新日期:2019-09-01 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::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:OBJECTIVE:Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2015.01.010
更新日期:2015-02-03 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: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: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: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 biol...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.12.001
更新日期:2020-02-01 00:00:00
abstract:OBJECTIVE:Adaptive thermogenesis, which is partly mediated by sympathetic input on brown adipose tissue (BAT), is a mechanism of heat production that confers protection against prolonged cold exposure. Various endogenous stimuli, for example, norepinephrine and FGF-21, can also promote the conversion of inguinal white ...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2020.101052
更新日期:2020-11-01 00:00:00
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 prot...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2018.08.003
更新日期:2018-11-01 00:00:00
abstract:OBJECTIVE:Brown adipose tissue (BAT) thermogenesis depends on the mobilization and oxidation of fatty acids from intracellular lipid droplets (LD) within brown adipocytes (BAs); however, the identity and function of LD proteins that control BAT lipolysis remain incomplete. Proteomic analysis of mouse BAT subcellular fr...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2017.10.014
更新日期:2018-01-01 00:00:00
abstract:OBJECTIVE:Pancreatic β cell failure plays a central role in the development of type 2 diabetes (T2D). While the transcription factors shaping the β cell gene expression program have received much attention, the post-transcriptional controls that are activated in β cells during stress are largely unknown. We recently id...
journal_title:Molecular metabolism
pub_type: 杂志文章
doi:10.1016/j.molmet.2019.05.009
更新日期:2019-08-01 00:00:00