RESUMEN
Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.
RESUMEN
The TGFß cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor 15 de Diferenciación de Crecimiento/farmacología , Neuronas/fisiología , Núcleos Parabraquiales/fisiología , Animales , Peso Corporal , Femenino , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Masculino , Ratones , Neuronas/efectos de los fármacos , Núcleos Parabraquiales/efectos de los fármacos , Ratas , Ratas Long-EvansRESUMEN
Deoxynivalenol (DON), a type B trichothecene mycotoxin contaminating grains, promotes nausea, emesis and anorexia. With DON exposure, circulating levels of intestinally derived satiation hormones, including glucagon-like peptide 1 (GLP-1) are elevated. To directly test whether GLP-1 signaling mediates the effects of DON, we examined the response of GLP-1 or GLP-1R-deficient mice to DON injection. We found comparable anorectic and conditioned taste avoidance learning responses in GLP-1/GLP-1R deficient mice compared to control littermates, suggesting that GLP-1 is not necessary for the effects of DON on food intake and visceral illness. We then used our previously published data from translating ribosome affinity purification with RNA sequencing (TRAP-seq) analysis of area postrema neurons that express the receptor for the circulating cytokine growth differentiation factor (GDF15), growth differentiation factor a-like (GFRAL). Interestingly, this analysis showed that a cell surface receptor for DON, calcium sensing receptor (CaSR), is heavily enriched in GFRAL neurons. Given that GDF15 potently reduces food intake and can cause visceral illness by signaling through GFRAL neurons, we hypothesized that DON may also signal by activating CaSR on GFRAL neurons. Indeed, circulating GDF15 levels are elevated after DON administration but both GFRAL knockout and GFRAL neuron-ablated mice exhibited similar anorectic and conditioned taste avoidance responses compared to WT littermates. Thus, GLP-1 signaling and GFRAL signaling and neurons are not required for DON-induced visceral illness or anorexia.
RESUMEN
Growth differentiation factor 15 (GDF15), a TGFß superfamily cytokine, acts through its receptor, cell line-derived neurotrophic factorfamily receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis-associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiological responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat, and human. However, we did not detect differences in LPS-induced anorexia between WT and GDF15KO or GFRALKO mice. Furthermore, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS-treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.NEW & NOTEWORTHY Although many responses to LPS depend on housing temperature, the anorexic response to LPS does not. LPS results in a potent and rapid increase in circulating levels of GDF15 in mice, rats, and humans. Nevertheless, GDF15 and its receptor (GFRAL) are not required for the anorexic response to systemic LPS administration. The anorexic response to LPS likely involves a myriad of complex physiological alterations.
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Anorexia/metabolismo , Factor 15 de Diferenciación de Crecimiento/efectos de los fármacos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Lipopolisacáridos/farmacología , Animales , Ingestión de Alimentos/efectos de los fármacos , Humanos , Ratones , Náusea/inducido químicamente , Ratas , Pérdida de Peso/efectos de los fármacosRESUMEN
The synergism of infection with conventional cardiovascular risk factors in atherosclerosis is much debated. We hypothesized that coronary arterial injury correlates with infection recurrence and pathogen burden and is further aggravated by hypercholesterolemia. Forty-two Göttingen minipigs were assigned to repeated intratracheal inoculation of PBS, Chlamydia pneumoniae (Cpn), or both Cpn and influenza virus at 8, 11, and 14 wk of age. Animals were fed either standard or 2% cholesterol diet (chol-diet). At 19 wk of age coronary vasomotor responses to acetylcholine (ACh) and adenosine were assessed in vivo and blood and tissue samples were collected. Nonparametric tests were used to compare the groups. In cholesterol-fed animals, total cholesterol/HDL was significantly increased in infected animals compared with noninfected animals [3.13 (2.17-3.38) vs. 2.03 (1.53-2.41), respectively; P = 0.01]. C-reactive protein (CRP) rose in infected animals [10.60 (4.96-18.00) vs. 2.47 (1.44-3.01) µg/ml in noninfected; P < 0.01] without significant difference between the mono- and coinfected groups. Among coinfected animals, both CRP and haptoglobin were lower in those fed chol-diet than in those fed standard diet (P < 0.05). The vasoconstricting response to ACh was most prominent in coinfected animals {769.3 (594-1,129) cm; P = 0.03 vs. noninfected [342 (309-455) cm] and P = 0.07 vs. monoinfected [415 (252.5-971.8) cm]}. Among monoinfected animals, similar to CRP, a trend for less vasoconstriction was observed in those fed chol-diet (P = 0.08). Coinfection of piglets appears to be associated with more pronounced coronary muscarinic vasomotor dysfunction. In monoinfected animals, use of chol-diet seems to dampen both coronary dysfunction and systemic inflammation induced by infection.
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Infecciones por Chlamydia/complicaciones , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/fisiopatología , Hipercolesterolemia/complicaciones , Inflamación/complicaciones , Infecciones por Orthomyxoviridae/complicaciones , Sistema Vasomotor/fisiopatología , Animales , Proteína C-Reactiva/metabolismo , Chlamydia , Infecciones por Chlamydia/sangre , Infecciones por Chlamydia/epidemiología , Comorbilidad , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Modelos Animales de Enfermedad , Hipercolesterolemia/sangre , Hipercolesterolemia/epidemiología , Inflamación/sangre , Inflamación/epidemiología , Masculino , Orthomyxoviridae , Infecciones por Orthomyxoviridae/sangre , Infecciones por Orthomyxoviridae/epidemiología , Recurrencia , Factores de Riesgo , Porcinos , Porcinos Enanos , Vasodilatadores/farmacología , Sistema Vasomotor/efectos de los fármacosRESUMEN
Vitamin C deficiency - or hypovitaminosis C defined as a plasma concentration below 23 µm - is estimated to affect hundreds of millions of people in the Western world, in particular subpopulations of low socio-economic status that tend to eat diets of poor nutritional value. Recent studies by us have shown that vitamin C deficiency may result in impaired brain development. Thus, the aim of the present study was to investigate if a poor diet high in fat and cholesterol affects the vitamin C status of guinea pigs kept on either sufficient or deficient levels of dietary ascorbate (Asc) for up to 6 months with particular emphasis on the brain. The present results show that a high-fat and cholesterol diet significantly decreased the vitamin C concentrations in the brain, irrespective of the vitamin C status of the animal (P < 0·001). The brain Asc oxidation ratio only depended on vitamin C status (P < 0·0001) and not on the dietary lipid content. In plasma, the levels of Asc significantly decreased when vitamin C in the diet was low or when the fat/cholesterol content was high (P < 0·0001 for both). The Asc oxidation ratio increased both with low vitamin C and with high fat and cholesterol content (P < 0·0001 for both). We show here for the first time that vitamin C homoeostasis of brain is affected by a diet rich in fat and cholesterol. The present findings suggest that this type of diet increases the turnover of Asc; hence, individuals consuming high-lipid diets may be at increased risk of vitamin C deficiency.
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Antioxidantes/metabolismo , Deficiencia de Ácido Ascórbico/metabolismo , Ácido Ascórbico/metabolismo , Encéfalo/efectos de los fármacos , Colesterol en la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/sangre , Deficiencia de Ácido Ascórbico/sangre , Encéfalo/metabolismo , Colesterol en la Dieta/sangre , Enfermedad Crónica , Grasas de la Dieta/sangre , Modelos Animales de Enfermedad , Cobayas , Homeostasis , Oxidación-ReducciónRESUMEN
While numerous techniques can be used to measure and analyze insulin secretion in isolated islets in culture, assessments of insulin secretion in vivo are typically indirect and only semiquantitative. The CpepSfGFP reporter mouse line allows the in vivo imaging of insulin secretion from individual islets after a glucose stimulation, in live, anesthetized mice. Imaging the whole pancreas at high resolution in live mice to track the response of each individual islet over time includes numerous technical challenges and previous reports were only limited in scope and non-quantitative. Elaborating on this previous model-through the development of an improved methodology addressing anesthesia, temperature control and motion blur-we were able to track and quantify longitudinally insulin content throughout a glucose challenge in up to two hundred individual islets simultaneously. Through this approach we demonstrate quantitatively for the first time that while isolated islets respond homogeneously to glucose in culture, their profiles differ significantly in vivo. Independent of size or location, some islets respond sharply to a glucose stimulation while others barely secrete at all. This platform therefore provides a powerful approach to study the impact of disease, diet, surgery or pharmacological treatments on insulin secretion in the intact pancreas in vivo.
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Glucosa/farmacología , Secreción de Insulina/efectos de los fármacos , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Imagen Molecular/métodos , Edulcorantes/farmacología , Animales , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
It is generally accepted that the addition of vitamin C to cell culture medium improves cell growth. However, once added, the vitamin C concentration declines rapidly. This situation differs from the in vivo environment where the endothelium is constantly supplied with ascorbate from the blood. With a focus on intracellular vitamin C, we simulated constant supply of ascorbate by the hourly addition of freshly prepared medium containing 75 microM ascorbate and subsequently compared it with more practical regimens using combinations of ascorbate and 2-phosphoascorbate. We found that a single supplement of ascorbate and 2-phosphoascorbate adequately maintains intracellular vitamin C at physiological levels for up to 72 h.
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Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/metabolismo , Técnicas de Cultivo de Célula , Ácido Ascórbico/química , Células Cultivadas , Células Endoteliales/metabolismo , Humanos , Factores de TiempoRESUMEN
To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems.
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Ingestión de Alimentos , Metabolismo Energético , Neuronas/metabolismo , Receptores de Calcitonina/fisiología , Núcleo Solitario/metabolismo , Animales , Peso Corporal , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/citología , Núcleo Solitario/citologíaRESUMEN
OBJECTIVE: Analogues of GDF15 (Growth Differentiation Factor 15) are promising new anti-obesity therapies as pharmacological treatment with GDF15 results in dramatic reductions of food intake and body weight. GDF15 exerts its central anorexic effects by binding to the GFRAL receptor exclusively expressed in the Area Postrema (AP) and the Nucleus of the Solitary Tract (NTS) of the hindbrain. We sought to determine if GDF15 is an indispensable factor for other interventions that cause weight loss and which are also known to act via these hindbrain regions. METHODS: To explore the role of GDF15 on food choice we performed macronutrient intake studies in mice treated pharmacologically with GDF15 and in mice having either GDF15 or GFRAL deleted. Next we performed vertical sleeve gastrectomy (VSG) surgeries in a cohort of diet-induced obese Gdf15-null and control mice. To explore the anatomical co-localization of neurons in the hindbrain responding to GLP-1 and/or GDF15 we used GLP-1R reporter mice treated with GDF15, as well as naïve mouse brain and human brain stained by ISH and IHC, respectively, for GLP-1R and GFRAL. Lastly we performed a series of food intake experiments where we treated mice with targeted genetic disruption of either Gdf15 or Gfral with liraglutide; Glp1r-null mice with GDF15; or combined liraglutide and GDF15 treatment in wild-type mice. RESULTS: We found that GDF15 treatment significantly lowered the preference for fat intake in mice, whereas no changes in fat intake were observed after genetic deletion of Gdf15 or Gfral. In addition, deletion of Gdf15 did not alter the food intake or bodyweight after sleeve gastrectomy. Lack of GDF15 or GFRAL signaling did not alter the ability of the GLP-1R agonist liraglutide to reduce food intake. Similarly lack of GLP-1R signaling did not reduce GDF15's anorexic effect. Interestingly, there was a significant synergistic effect on weight loss when treating wild-type mice with both GDF15 and liraglutide. CONCLUSION: These data suggest that while GDF15 does not play a role in the potent effects of VSG in mice there seems to be a potential therapeutic benefit of activating GFRAL and GLP-1R systems simultaneously.
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Cirugía Bariátrica , Factor 15 de Diferenciación de Crecimiento/metabolismo , Factor 15 de Diferenciación de Crecimiento/uso terapéutico , Hipoglucemiantes/uso terapéutico , Liraglutida/uso terapéutico , Obesidad/tratamiento farmacológico , Pérdida de Peso/efectos de los fármacos , Animales , Área Postrema/metabolismo , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Sinergismo Farmacológico , Ingestión de Alimentos/efectos de los fármacos , Gastrectomía , Eliminación de Gen , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Factor 15 de Diferenciación de Crecimiento/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/etiología , Núcleo Solitario/metabolismoRESUMEN
BACKGROUND: One-anastomosis gastric bypass (OAGB) and single-anastomosis duodenal switch (SADS) have become increasingly popular weight loss strategies. However, data directly comparing the effectiveness of these procedures with Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) are limited. OBJECTIVES: To examine the metabolic outcomes of OAGB, SADS, RYGB, and SG in a controlled rodent model. SETTING: Academic research laboratory, United States. METHODS: Surgeries were performed in diet-induced obese Long-Evans rats, and metabolic outcomes were monitored before and for 15 weeks after surgery. RESULTS: All bariatric procedures induced weight loss compared with sham that lasted throughout the course of the study. The highest percent fat loss occurred after OAGB and RYGB. All bariatric procedures had improved glucose dynamics associated with an increase in insulin (notably OAGB and SADS) and/or glucagon-like protein-1 secretion. Circulating cholesterol was reduced in OAGB, SG, and RYGB. OAGB and SG additionally decreased circulating triglycerides. Liver triglycerides were most profoundly reduced after OAGB and RYGB. Circulating iron levels were decreased in all surgical groups, associated with a decreased hematocrit value and increased reticulocyte count. The fecal microbiome communities of OAGB, SADS, and RYGB were significantly altered; however, SG exhibited no change in microbiome diversity or composition. CONCLUSIONS: These data support the use of the rat for modeling bariatric surgical procedures and highlight the ability of the OAGB to meet or exceed the metabolic improvements of RYGB. These data point to the likelihood that each surgery accomplishes metabolic improvements through both overlapping and distinct mechanisms and warrants further research.
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Anastomosis en-Y de Roux/estadística & datos numéricos , Glucemia , Gastrectomía/estadística & datos numéricos , Derivación Gástrica/estadística & datos numéricos , Obesidad , Animales , Glucemia/análisis , Glucemia/metabolismo , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/fisiología , Masculino , Obesidad/sangre , Obesidad/cirugía , Ratas , Ratas Long-Evans , Estados UnidosRESUMEN
OBJECTIVE: In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. METHODS: We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. RESULTS: We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c- macrophages, increased frequencies of T cells (CD4+, CD8+, and CD4-/CD8- T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. CONCLUSIONS: These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss.
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Tejido Adiposo/inmunología , Gastrectomía/efectos adversos , Macrófagos/inmunología , Complicaciones Posoperatorias/inmunología , Linfocitos T/inmunología , Tejido Adiposo/patología , Animales , Relación CD4-CD8 , Células Dendríticas/inmunología , Gastrectomía/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Complicaciones Posoperatorias/patología , Pérdida de PesoRESUMEN
Vitamin C deficiency globally affects several hundred million people and has been associated with increased morbidity and mortality in numerous studies. In this study, bioavailability of the oxidized form of vitamin C (l-dehydroascorbic acid or DHA)-commonly found in vitamin C containing food products prone to oxidation-was studied. Our aim was to compare tissue accumulation of vitamin C in guinea pigs receiving different oral doses of either ascorbate or DHA. In all tissues tested (plasma, liver, spleen, lung, adrenal glands, kidney, muscle, heart, and brain), only sporadic differences in vitamin C accumulation from ascorbate or DHA were observed except for the lowest dose of DHA (0.25mg/ml in the drinking water), where approximately half of the tissues had slightly yet significantly less vitamin C accumulation than from the ascorbate source. As these results contradicted data from rats, we continued to explore the ability to recycle DHA in blood, liver and intestine in guinea pigs, rats and mice. These investigations revealed that guinea pigs have similar recycling capacity in red blood cells as observed in humans, while rats and mice do not have near the same ability to reduce DHA in erythrocytes. In liver and intestinal homogenates, guinea pigs also showed a significantly higher ability to recycle DHA compared to rats and mice. These data demonstrate that DHA in guinea pigs-as in humans-is almost as effective as ascorbate as vitamin C source when it comes to taking up and storing vitamin C and further suggest that the guinea pig is superior to other rodents in modeling human vitamin C homeostasis.
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Ácido Ascórbico/administración & dosificación , Ácido Deshidroascórbico/administración & dosificación , Intestinos/química , Hígado/química , Vitaminas/administración & dosificación , Animales , Ácido Ascórbico/farmacocinética , Deficiencia de Ácido Ascórbico/tratamiento farmacológico , Ácido Deshidroascórbico/farmacocinética , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Eritrocitos/química , Cobayas , Humanos , Ratones , Ratas , Distribución Tisular , Vitaminas/farmacocinéticaRESUMEN
In addition to lowering of blood glucose, treatment with insulin also induces lipid synthesis and storage. Patients with type 2 diabetes often suffer from lipid-related comorbidities including dyslipidemia, obesity, and fatty liver disease. We examined here in two separate studies changes in lipid dynamics in Zucker diabetic fatty (ZDF) rats, in response to 7 days of treatment with either insulin or the insulin receptor agonist peptide S597. In concert with blood glucose normalization, the treated rats displayed large increases in hepatic de novo lipid synthesis and deposition of newly synthesized lipids in adipose tissue depots, accompanied by weight gain and expansion of adipose depots. In both treatment groups, heavy water labeling revealed that after 2 h (study A), de novo lipogenesis was responsible for 80% of newly stored hepatic triglyceride (TG)-palmitate, and after 5 days (study B), â¼60% of newly deposited TG-palmitate in adipose tissues originated from this pathway. Interestingly, in both studies, treatment with the insulin mimetic peptide resulted in significantly lower blood TG levels, plasma TG production rates, and hepatic de novo synthesized fatty acid in plasma TG compared with insulin. There were no differences in plasma TG turnover (clearance rate) in response to either treatment, consistent with differential actions on the liver. These results show that in ZDF rats, treatment with a synthetic insulin-receptor-activating peptide or with insulin to lower blood glucose is accompanied by different effects on hepatic lipid anabolism and blood TG profiles.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Receptor de Insulina/agonistas , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Péptidos/uso terapéutico , RatasRESUMEN
Insulin treatment is associated with increased adipose mass in both humans and mice. However, the underlying dynamic basis of insulin induced lipid accumulation in adipose tissue remains elusive. To assess this, young female C57BL6/J mice were fed a low fat diet for 3 weeks, treated subsequently with 7 days of constant subcutaneous insulin infusion by osmotic minipumps and compared to mice with only buffer infused. To track changes in lipid deposition during insulin treatment, metabolic labeling was conducted with heavy water for the final 4 days. Blood glucose was significantly lowered within one hour after implantation of insulin loaded mini pumps and remained lower throughout the study. Insulin treated animals gained significantly more weight during treatment and the mean weight of the subcutaneous adipose depots was significantly higher with the highest dose of insulin. Surprisingly, de novo palmitate synthesis within the subcutaneous and the gonadal depots was not affected significantly by insulin treatment. In contrast insulin treatment caused accumulation of triglycerides in both depots due to either deposition of newly synthesised triglycerides (subcutaneous depot) or inhibition of lipolysis (gonadal depot).
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Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/crecimiento & desarrollo , Insulina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Palmitatos/metabolismo , Animales , Glucemia , Peso Corporal , Conducta Alimentaria/efectos de los fármacos , Femenino , Insulina/administración & dosificación , Lipólisis , Ratones , Tamaño de los Órganos/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
Exposure to particulate matter is associated with oxidative stress and risk of cardiovascular diseases. We investigated if vitamin C and desferrioxamine (iron chelator) altered the levels of oxidative stress and expression of cell adhesion molecules upon exposure to diesel exhaust particles (DEP) and carbon black in cultured human umbilical vein endothelial cells (HUVECs). We found that the particles were only slightly cytotoxic in the high concentration ranges. Particle-induced intracellular reactive oxygen species (ROS) production was attenuated by vitamin C administration or iron chelation and particularly when combined (p<0.001). Only desferrioxamine protected the DNA from oxidative damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sensitive sites induced by carbon black (p<0.01). Carbon black and small sized DEP generated from an Euro4 engine increased the surface expression of VCAM-1 and ICAM-1, whereas DEP from an engine representing an old combustion type engine (SRM2975) with larger particles did not affect the expression of cell adhesion molecules. These effects were also attenuated by desferrioxamine but not vitamin C. The study shows that exposure to carbon black and DEP in HUVECs can generate both oxidative stress and expression of cell surface adhesion molecules and that these effects can in part be attenuated by vitamin C and desferrioxamine.
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Ácido Ascórbico/farmacología , Células Endoteliales/efectos de los fármacos , Quelantes del Hierro/farmacología , Estrés Oxidativo , Hollín/toxicidad , Emisiones de Vehículos/toxicidad , Células Cultivadas , Daño del ADN , Deferoxamina/farmacología , Células Endoteliales/química , Células Endoteliales/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/análisis , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Molécula 1 de Adhesión Celular Vascular/análisisRESUMEN
INTRODUCTION: Muscarinic M(5) receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M(5) receptors modulate their activity. Previous studies showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs. MATERIALS AND METHODS: Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M (5) (-/-) mice backcrossed to the C57BL/6NTac strain. STATISTICAL ANALYSES: Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M (5) (-/-) mice, while the effects of cocaine were similar in M (5) (-/-) and wild-type mice. RESULTS: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M (5) (-/-) mice. DISCUSSION: The different effects of amphetamine and cocaine in M (5) (-/-) mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M(5) receptor. These results support the concept that the M(5) receptor modulates effects of addictive drugs.
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Anfetamina/farmacología , Cocaína/farmacología , Dopamina/metabolismo , Receptor Muscarínico M5/metabolismo , Animales , Inhibidores de Captación de Dopamina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Receptor Muscarínico M5/genéticaRESUMEN
Vitamin C is a pivotal redox modulater in many biological reactions of which several remain poorly understood. Naturally, vitamin C has been the subject of many investigations over the past decades in relation to its possible beneficial effects on cardiovascular disease primarily based on its powerful yet general antioxidant properties. However, growing epidemiological, clinical and experimental evidence now suggests a more specific role of ascorbate in vasomotion and in the prevention of atherosclerosis. For example, in contrast to most other biological antioxidants, administration of vitamin C can apparently induce vasodilation. Millions of people worldwide can be diagnosed with vitamin C deficiency according to accepted definitions. In this perspective, the present review examines the evidence for a specific link between vitamin C deficiency and increased risk of atherosclerosis as well as the possible mechanisms by which vitamin C may exert its protective function.