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1.
Nat Rev Endocrinol ; 17(8): 468-483, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34108679

RESUMO

Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.


Assuntos
Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Insulina/metabolismo , Doenças Metabólicas/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Homeostase/fisiologia , Humanos , Resistência à Insulina/fisiologia , Doenças Metabólicas/fisiopatologia , Síndrome Metabólica/metabolismo , Transdução de Sinais/fisiologia
2.
Sci Adv ; 6(23): eaaz1341, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32537493

RESUMO

ß-Arrestin-1 and ß-arrestin-2 have emerged as important signaling molecules that modulate glucose fluxes in several peripheral tissues. The potential roles of neuronally expressed ß-arrestins in regulating glucose homeostasis remain unknown. We here report that mice lacking ß-arrestin-1 (barr1) selectively in AgRP neurons displayed impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet, while mice overexpressing barr1 selectively in AgRP neurons were protected against obesity-associated metabolic impairments. Additional physiological, biochemical, and electrophysiological data indicated that the presence of barr1 is essential for insulin-mediated hyperpolarization of AgRP neurons. As a result, barr1 expressed by AgRP neurons regulates efferent neuronal pathways that suppress hepatic glucose production and promote lipolysis in adipose tissue. Mice lacking ß-arrestin-2 (barr2) selectively in AgRP neurons showed no substantial metabolic phenotypes. Our data suggest that agents able to enhance the activity of barr1 in AgRP neurons may prove beneficial as antidiabetic drugs.

3.
Nat Commun ; 10(1): 2717, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222048

RESUMO

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.


Assuntos
Leptina/metabolismo , Fígado/metabolismo , Bulbo/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Infusões Intraventriculares , Injeções Intraventriculares , Leptina/administração & dosagem , Lipogênese/fisiologia , Lipoproteínas VLDL , Fígado/inervação , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Simpatectomia , Nervo Vago/fisiologia , Nervo Vago/cirurgia
4.
J Clin Endocrinol Metab ; 104(6): 2453-2461, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722035

RESUMO

CONTEXT: Although glucocorticoids (GCs) have potent anti-inflammatory actions, patients with hypercortisolism due to Cushing disease (CD) have increased circulating proinflammatory cytokines that may contribute to their insulin resistance and cardiovascular disease. The mechanisms and tissues that account for the increased systemic inflammation in patients with CD are unknown. OBJECTIVE: To determine whether chronic endogenous GC exposure due to CD is associated with adipose tissue (AT) inflammation in humans. DESIGN, SETTING, PARTICIPANTS: Abdominal subcutaneous AT samples from 10 patients with active CD and 10 age-, sex-, and body mass index‒matched healthy subjects were assessed for macrophage infiltration and mRNA expression of proinflammatory cytokines. MAIN OUTCOME MEASURE: Using immunohistochemistry, AT samples were analyzed for the expression of vimentin, caspase, CD3, CD4, CD8, CD11c, CD20, CD31, CD56, CD68, and CD163. Quantitative PCR was used to assess the mRNA gene expression of arginase, CD11b, CD68, EMR-1, IL-6, IL-10, MCP-1, and TNF-α. RESULTS: Immunohistochemistry revealed higher mean percentage infiltration of CD68+ macrophages and CD4+ T lymphocytes, increased mean area of CD11c+ M1 macrophages, higher number of CD11c+ crownlike structures, and decreased vimentin in the AT of patients with active CD compared with controls. PCR revealed no differences in mRNA expression of any analyzed markers in patients with CD. CONCLUSIONS: Chronic exposure to GCs due to CD increases the presence of AT macrophages, a hallmark of AT inflammation. Hence, AT inflammation may be the source of the systemic inflammation seen in CD, which in turn may contribute to obesity, insulin resistance, and cardiovascular disease in these patients.


Assuntos
Tecido Adiposo/patologia , Macrófagos/imunologia , Hipersecreção Hipofisária de ACTH/patologia , Adulto , Idoso , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígeno CD11c/análise , Citocinas/genética , Feminino , Humanos , Imuno-Histoquímica , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade
5.
PLoS Biol ; 17(2): e3000138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30730909

RESUMO

The sympathetic nervous system (SNS) controls key aspects of adipose tissue (AT) function through the release of norepinephrine (NE) and beta adrenergic signaling. Sympathetic tone is determined by NE release but also by the rate of extracellular NE clearance that historically has been believed to occur solely through solute carrier family 6 member 2 (SLC6A2) expressed on sympathetic neurons. Song and colleagues show that adipocytes can also clear NE through organic cation transporter 3 (Oct3). This contributes to our understanding of how adrenergic signaling is controlled in AT and also emphasizes the need to develop better methods to assess adrenergic signaling in vivo.


Assuntos
Catecolaminas , Norepinefrina , Adipócitos , Tecido Adiposo Branco , Cátions
6.
Mol Neurodegener ; 13(1): 33, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29945658

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer's disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD. METHODS: We have applied a newly developed protocol for deriving human basal forebrain cholinergic neurons (BFCN) from skin fibroblasts via induced pluripotent stem cell (iPSC) technology. We generated wildtype and familial AD mutant PSEN2 N141I (presenilin 2) BFCNs and assessed if insulin signaling, insulin regulation of the major AD proteins Aß and/or tau, and/or calcium fluxes is altered by the PSEN2 N141I mutation. RESULTS: We report herein that wildtype, PSEN2 N141I and CRISPR/Cas9-corrected iPSC-derived BFCNs (and their precursors) show indistinguishable insulin signaling profiles as determined by the phosphorylation of canonical insulin signaling pathway molecules. Chronic insulin treatment of BFCNs of all genotypes led to a reduction in the Aß42/40 ratio. Unexpectedly, we found a CRISPR/Cas9-correctable effect of PSEN2 N141I on calcium flux, which could be prevented by chronic exposure of BFCNs to insulin. CONCLUSIONS: Our studies indicate that the familial AD mutation PSEN2 N141I does not induce neuronal insulin resistance in a cell autonomous fashion. The ability of insulin to correct calcium fluxes and to lower Aß42/40 ratio suggests that insulin acts to oppose an AD-pathophysiology. Hence, our results are consistent with a potential physiological role for insulin as a mediator of resilience by counteracting specific metabolic and molecular features of AD.


Assuntos
Doença de Alzheimer/metabolismo , Neurônios Colinérgicos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Insulina/metabolismo , Doença de Alzheimer/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Mutação , Presenilina-2/genética
7.
Nat Rev Neurol ; 14(3): 168-181, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29377010

RESUMO

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.


Assuntos
Encéfalo/metabolismo , Demência/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Insulina/metabolismo , Humanos
8.
Biochim Biophys Acta Mol Basis Dis ; 1863(12): 3277-3285, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28962896

RESUMO

OBJECTIVE: The transcription factor Krüppel-like factor 14 (KLF14) has been associated with type 2 diabetes and high-density lipoprotein-cholesterol (HDL-C) through genome-wide association studies. The mechanistic underpinnings of KLF14's control of metabolic processes remain largely unknown. We studied the physiological roles of KLF14 in a knockout (KO) mouse model. METHODS: Male whole body Klf14 KO mice were fed a chow or high fat diet (HFD) and diet induced phenotypes were analyzed. Additionally, tissue-specific expression of Klf14 was determined using RT-PCR, RNA sequencing, immunoblotting and whole mount lacZ staining. Finally, the consequences of KLF14 loss-of-function were studied using RNA sequencing in tissues with relatively high Klf14 expression levels. RESULTS: KLF14 loss-of-function did not affect HFD-induced weight gain or insulin resistance. Fasting plasma concentrations of glucose, insulin, cholesterol, HDL-C and ApoA-I were also comparable between Klf14+/+ and Klf14-/- mice on chow and HFD. We found that in mice expression of Klf14 was the highest in the anterior pituitary (adenohypophysis), lower but detectable in white adipose tissue and undetectable in liver. Loss of KLF14 function impacted on the pituitary transcriptome with extracellular matrix organization as the primary affected pathway and a predicted link to glucocorticoid receptor signaling. CONCLUSIONS: Whole body loss of KLF14 function in male mice does not result in metabolic abnormalities as assessed under chow and HFD conditions. Mostly likely there is redundancy for the role of KLF14 in the mouse and a diverging function in humans.


Assuntos
Fatores de Transcrição Kruppel-Like/deficiência , Síndrome Metabólica/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Colesterol/metabolismo , HDL-Colesterol/metabolismo , Dieta Hiperlipídica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glucose/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Síndrome Metabólica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucocorticoides/metabolismo , Análise de Sequência de RNA
9.
Cell ; 171(4): 824-835.e18, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29056338

RESUMO

Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.


Assuntos
Proteína Forkhead Box O1/antagonistas & inibidores , Glucose/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina , Acetilação , Animais , Células Cultivadas , Proteína Forkhead Box O1/química , Glucoquinase/genética , Glucoquinase/metabolismo , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Células HEK293 , Hepatócitos/enzimologia , Histona Desacetilases/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fosforilação , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Complexo Correpressor Histona Desacetilase e Sin3
10.
Nature ; 546(7656): 107-112, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28538730

RESUMO

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.


Assuntos
Tecido Adiposo/metabolismo , Adiposidade , Subunidade beta do Hormônio Folículoestimulante/antagonistas & inibidores , Termogênese , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Subunidade beta do Hormônio Folículoestimulante/imunologia , Haploinsuficiência , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Obesidade/prevenção & controle , Osteoporose/tratamento farmacológico , Ovariectomia , Consumo de Oxigênio/efeitos dos fármacos , Receptores do FSH/antagonistas & inibidores , Receptores do FSH/genética , Receptores do FSH/metabolismo , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese
11.
Diabetes ; 66(6): 1560-1571, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28385803

RESUMO

Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet-induced hepatic steatosis.


Assuntos
Tecido Adiposo/metabolismo , Proteína Relacionada com Agouti/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptor de Insulina/genética , Tecido Adiposo/efeitos dos fármacos , Animais , Calorimetria Indireta , Temperatura Baixa , Dieta Hiperlipídica , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/metabolismo , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Hipotálamo/citologia , Hipotálamo/metabolismo , Insulina/farmacologia , Lipólise , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Insulina/metabolismo , Transdução de Sinais , Triglicerídeos/metabolismo
12.
Nat Med ; 23(5): 623-630, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28414329

RESUMO

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through ß3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1-/- and interleukin-4 receptor-α double-negative (Il4ra-/-) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Macrófagos/imunologia , Norepinefrina/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Termogênese/imunologia , Tirosina 3-Mono-Oxigenase/genética , Adaptação Fisiológica , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Western Blotting , Composição Corporal/imunologia , Catecolaminas/metabolismo , Diferenciação Celular , Meios de Cultivo Condicionados , Metabolismo Energético/genética , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Interleucina-4/imunologia , Interleucina-4/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores de Superfície Celular/genética , Termogênese/genética , Proteína Desacopladora 1/genética
13.
J Clin Endocrinol Metab ; 102(4): 1325-1332, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323986

RESUMO

Context: Nonalcoholic fatty liver disease and elevated circulating branched-chain amino acids (BCAAs) are common characteristics of obesity and type 2 diabetes. In rodents, brain insulin signaling controls both hepatic triglyceride secretion and BCAA catabolism. Whether brain insulin signaling controls similar metabolic pathways in humans is unknown. Objective: Here we assessed if intranasal insulin, a method to preferentially deliver insulin to the central nervous system, is able to modulate hepatic lipid content and plasma BCAAs in humans. Design/Setting: We conducted a randomized, double-blind, placebo-controlled trial at the Medical University of Vienna. Participants/Intervention: We assessed if a chronic 4-week intranasal insulin treatment (40 IU, 4 times daily) reduces hepatic triglyceride content and circulating BCAAs in 20 healthy male volunteers. Main Outcome Measures: Hepatic lipid content was assessed noninvasively by 1H-magnetic resonance spectroscopy, and BCAAs were measured by gas chromatography mass spectrometry at defined time points during the study. Results: Chronic intranasal insulin treatment did not alter body weight, body mass index, and hepatic lipid content but reduced circulating BCAA levels. Conclusions: These findings support the notion that brain insulin controls BCAA metabolism in humans. Thus, brain insulin resistance could account at least in part for the elevated BCAA levels observed in the insulin-resistant state.


Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Insulina/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Administração Intranasal , Adulto , Método Duplo-Cego , Regulação para Baixo , Esquema de Medicação , Voluntários Saudáveis , Humanos , Insulina/efeitos adversos , Lipídeos/análise , Fígado/química , Masculino , Placebos
14.
J Clin Invest ; 127(2): 450-453, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28112680

RESUMO

Insulin replacement is the cornerstone of type 1 diabetes (T1D) treatment; however, glycemic control remains a challenge. Leptin has been shown to effectively restore euglycemia in rodent models of T1D; however, the mechanism or mechanisms by which leptin exerts glycemic control are unclear. In this issue of the JCI, Perry and colleagues provide evidence that suppression of lipolysis is a key facet of leptin-mediated restoration of euglycemia. However, more work remains to be done to fully understand the antidiabetic mechanisms of leptin.


Assuntos
Diabetes Mellitus Tipo 1 , Leptina/uso terapêutico , Lipólise/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Insulina/uso terapêutico
15.
Clin Endocrinol (Oxf) ; 86(1): 68-74, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27630017

RESUMO

CONTEXT: Inflammation contributes to the development of metabolic and cardiovascular disease. Cushing's disease (CD), a state of chronic glucocorticoid (GC) excess characterized by visceral obesity and insulin resistance, may be associated with increased systemic inflammation. Cardiovascular mortality in CD remains elevated even after successful remission. It is unclear whether a chronic low-grade inflammatory state persists even after remission of CD, which may account for the increased CVD mortality. PURPOSE: (1) To assess circulating proinflammatory cytokines in patients with active CD and BMI-matched controls; (2) to prospectively follow plasma cytokine concentrations in patients with CD before and after surgical remission; and (3) to assess whether plasma cytokine concentrations correlate with adipose tissue distribution and ectopic lipid content in liver and muscle. METHODS: Plasma cytokines from prospectively enrolled patients with CD (N = 31) were quantified during active disease (v1) vs controls (N = 18) and 19·5 ± 12·9 months after surgical remission (v2). Fasting plasma IL-6, IL-1ß, TNF-α, IL-8, IL-17 and IL-10 were quantified using a multiplex assay. Total and regional fat masses were measured by whole-body MRI. RESULTS: Circulating IL-6 and IL-1ß were elevated in patients with active CD vs controls (P < 0·05) and remained elevated in CD after surgical remission, despite decreases in BMI (P < 0·001), HOMA-IR (P < 0·001), and visceral, hepatic and intermuscular fat (P < 0·001, <0·001 and 0·03, respectively). CONCLUSIONS: Despite long-term remission and improvements in fat distribution and insulin sensitivity, patients with CD may suffer from a state of chronic low-grade inflammation, which could contribute to increased cardiovascular mortality.


Assuntos
Citocinas/sangue , Hipersecreção Hipofisária de ACTH/sangue , Adiposidade , Adulto , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/cirurgia , Estudos Prospectivos , Análise de Regressão , Indução de Remissão
16.
Neuropeptides ; 64: 75-83, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28024880

RESUMO

Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase-expressing transgenic mice. Adult male and female mice, with conditional ablation of the Vgf gene in embryonic neurons had significantly reduced body weight, increased energy expenditure, and were resistant to diet-induced obesity. Conditional forebrain postnatal ablation of VGF in male mice, primarily in adult excitatory neurons, had no measurable effect on body weight nor on energy expenditure, but led to a modest increase in adiposity, partially overlapping the effect of AAV-Cre-mediated targeted ablation of VGF in the adult ventromedial hypothalamus and arcuate nucleus of floxed Vgf mice (Foglesong et al., 2016), and also consistent with results of icv delivery of the VGF-derived peptide TLQP-21 to adult mice, which resulted in increased energy expenditure and reduced adiposity (Bartolomucci et al., 2006). Because the lean, hypermetabolic phenotype of germline VGF knockout mice is to a great extent recapitulated in Syn-Cre+/-,Vgfflpflox/flpflox mice, we conclude that the metabolic profile of germline VGF knockout mice is largely the result of VGF ablation in embryonic CNS neurons, rather than peripheral endocrine and/or neuroendocrine cells, and that in forebrain structures such as hypothalamus, VGF and/or VGF-derived peptides play uniquely different roles in the developing and adult nervous system.


Assuntos
Peso Corporal/fisiologia , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Neuropeptídeos/metabolismo , Animais , Dieta , Metabolismo Energético/genética , Camundongos , Fatores de Crescimento Neural , Neurônios/metabolismo , Obesidade/metabolismo
17.
Environ Health Perspect ; 124(11): 1722-1727, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27325568

RESUMO

BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. OBJECTIVE: We hypothesized that perinatal DDT exposure causes hypertension in adult mice. METHODS: DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. RESULTS: Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. CONCLUSIONS: These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722-1727; http://dx.doi.org/10.1289/EHP164.


Assuntos
Cardiomegalia/induzido quimicamente , DDT/toxicidade , Exposição Ambiental , Hipertensão/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Pressão Sanguínea , Captopril/uso terapêutico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
18.
Alzheimers Dement ; 12(8): 851-61, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26928090

RESUMO

INTRODUCTION: Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. METHODS: We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. RESULTS: APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. DISCUSSION: Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Aminoácidos de Cadeia Ramificada/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Doenças Metabólicas/etiologia , Transdução de Sinais/fisiologia , Doença de Alzheimer/genética , Aminoácidos de Cadeia Ramificada/sangue , Precursor de Proteína beta-Amiloide/genética , Animais , Peso Corporal/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Alimentos/genética , Regulação da Expressão Gênica/genética , Humanos , Hipotálamo/fisiopatologia , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Triglicerídeos/metabolismo
19.
Diabetes ; 65(6): 1511-20, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26861781

RESUMO

Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis.


Assuntos
Encéfalo/metabolismo , Insulina/fisiologia , Fígado/metabolismo , Transdução de Sinais/fisiologia , Triglicerídeos/metabolismo , Animais , Fígado Gorduroso/fisiopatologia , Lipoproteínas VLDL/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
20.
Acta Neuropathol Commun ; 4: 16, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26916443

RESUMO

INTRODUCTION: Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer's disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice. RESULTS: Male mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (Aß) peptide. CONCLUSIONS: In general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Receptores de Superfície Celular/deficiência , Aminoácidos de Cadeia Ramificada/sangue , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/genética , Animais , Composição Corporal/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Resistência à Insulina , Lipídeos/sangue , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Fenótipo , Presenilina-1/genética , Receptores de Superfície Celular/genética , Fatores Sexuais
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