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G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1ß and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1ß. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions.
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Ácidos Graxos Ômega-3 , Microglia , Receptores Acoplados a Proteínas G , Adulto , Animais , Humanos , Camundongos , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Doenças Neuroinflamatórias , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Understanding how obesity rewires the brain, triggers neuroinflammation and neurodegeneration relies on research using animal models. There is, however, a disconnect between the timeline of human obesity and typical preclinical protocols. We emphasize here the need to adopt models of chronic obesity to study the pathophysiology of human obesity.
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Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.
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Núcleo Arqueado do Hipotálamo , Leptina , Camundongos , Animais , Feminino , Leptina/metabolismo , Estradiol/farmacologia , Pró-Opiomelanocortina/metabolismo , Hipotálamo/metabolismo , Obesidade/metabolismoRESUMO
Over the last three decades, neurodegenerative diseases have received increasing attention due to their frequency in the aging population and the social and economic burdens they are posing. In parallel, an era's worth of research in neuroscience has shaped our current appreciation of the complex relationship between nutrition and the central nervous system. Particular branches of nutrition continue to galvanize neuroscientists, in particular the diverse roles that bioactive food derivatives play on health and disease. Bioactive food derivatives are nowadays recognized to directly impact brain homeostasis, specifically with respect to their actions on cellular mechanisms of oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis and autophagy. However, ambiguities still exist regarding the significance of the influence of bioactive food derivatives on human health. In turn, gut microbiota dysbiosis is emerging as a novel player in the pathogenesis of neurodegenerative diseases. Currently, several routes of communication exist between the gut and the brain, where molecules are either released in the bloodstream or directly transported to the CNS. As such, bioactive food derivatives can modulate the complex ecosystem of the gut-brain axis, thus, targeting this communication network holds promises as a neuroprotective tool. This review aims at addressing one of the emerging aspects of neuroscience, particularly the interplay between food bioactive derivatives and neurodegeneration. We will specifically address the role that polyphenols and omega-3 fatty acids play in preventing neurodegenerative diseases and how dietary intervention complements available pharmacological approaches.
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Doenças Neurodegenerativas , Probióticos , Humanos , Idoso , Neuroproteção , Ecossistema , Disbiose , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , EncéfaloRESUMO
Obesity significantly increases the risk for anxiety and depression. Our group has recently demonstrated a role for nucleus accumbens (NAc) pro-inflammatory nuclear factor kappa-B (NFkB) signaling in the development of anxiodepressive-like behaviors by diet-induced obesity in male mice. The NAc is a brain region involved in goal-oriented behavior and mood regulation whose functions are critical to hedonic feeding and motivation. While the incidence of depression and anxiety disorders is significantly higher in women than in men, the use of female animal models in psychiatric research remains limited. We set out to investigate the impact of chronic intake of saturated and monounsaturated high-fat diets (HFD) on energy metabolism and on anxiety- and despair-like behaviors in female mice and to ascertain the contribution of NAc NFkB-mediated inflammation herein. Adult C57Bl6N female mice were fed either a saturated HFD, an isocaloric monounsaturated HFD or a control low-fat diet for 24 weeks, after which metabolic profiling and behavioral testing for anxiodepressive-like behaviors were conducted. Plasma was collected at time of sacrifice for quantification of leptin, inflammatory markers as well as 17 ß-estradiol levels and brains were harvested to analyze NAc expression of pro-inflammatory genes and estrogen-signaling molecules. In another group of female mice placed on the saturated HFD or the control diet for 24 weeks, we performed adenoviral-mediated invalidation of the NFkB signaling pathway in the NAc prior to behavioral testing. While both HFDs provoked obesity and metabolic impairments, only the saturated HFD triggered anxiodepressive-like behaviors and caused marked elevations in plasma estrogen. This saturated HFD-specific behavioral phenotype could not be explained by NAc inflammation alone and was unaffected by NAc invalidation of the NFkB signaling pathway. Instead, we found changes in the expression of estrogen signaling markers. Such results diverge from the inflammatory mechanisms underlying diet- and obesity-induced metabolic dysfunction and anxiodepressive-like behavior onset in male mice and call attention to the role of estrogen signaling in diet-related anxiodepressive-like phenotypes in female mice.
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BACKGROUND: Pharmacotherapies targeting motivational aspects of feeding and palatable food reward, while sparing mood and cognitive function, represent an alluring approach to reverse obesity and maintain weight loss in an obesogenic environment. A novel glucagon-like peptide-1/dexamethasone (GLP-1/Dexa) conjugate, developed to selectively activate glucocorticoid receptors in GLP-1 receptor-expressing cells was shown to decrease food intake and lower body weight in obese mice. Here, we investigate if this novel drug candidate modulates the rewarding properties of food and if it affects behavioral indices of mood and memory. METHODS: C57Bl6 mice treated with the GLP-1/Dexa conjugate, GLP-1 or vehicle lever-pressed for high-fat, high sugar (HFHS) food rewards in an operant task. Alterations in food-motivated behavior were also assessed following a HFHS diet withdrawal manipulation (switch to chow). The effects of repeated GLP-1/Dexa conjugate, GLP-1 or vehicle on free-feeding intake, body weight, anxiodepressive behaviors (elevated-plus maze, open field test & forced swim test), memory (novel object recognition) and mRNA expression of reward-relevant markers in the nucleus accumbens were also evaluated in mice fed a HFHS diet for 12 weeks. RESULTS: Mice treated with a GLP-1 analogue displayed a transient (4â¯h) reduction in their motivation to lever press for HFHS reward, whereas treatment with equimolar doses of GLP-1/Dexa delivered a superior and sustained (20â¯h) suppression of food-motivated behavior. GLP-1/Dexa also inhibited food reward following withdrawal from the HFHS diet. These benefits coincided with related transcriptional changes of dopaminergic markers in the nucleus accumbens. Importantly, repeated GLP-1/Dexa treatment during a HFHS diet caused weight loss without affecting anxiodepressive behavior and memory. CONCLUSION: Via its actions to blunt the rewarding effects of palatable food without affecting mood and recognition memory, GLP-1-directed targeting of dexamethasone may serve as a promising and safe anti-obesity strategy.
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Afeto/efeitos dos fármacos , Dexametasona/farmacologia , Alimentos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Memória/efeitos dos fármacos , Motivação/efeitos dos fármacos , Recompensa , Animais , Condicionamento Operante/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , CamundongosRESUMO
Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neurons remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, whereas human TBX3 haploinsufficiency has been linked with obesity. Here, we demonstrate that loss of Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both the peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed after loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated mouse neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a key mechanistic process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism.
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Hipotálamo/metabolismo , Melanocortinas/metabolismo , Neurônios/metabolismo , Proteínas com Domínio T/metabolismo , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Peso Corporal , Metabolismo Energético , Perfilação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Hipotálamo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/genética , RNA Mensageiro/genética , Proteínas com Domínio T/genéticaRESUMO
Insufficient dietary intake of essential omega-3 polyunsaturated fatty acids (N-3), especially during critical stages of development, is well-associated with negative neurological and metabolic consequences. The increased availability and intake of foods rich in saturated fat coincides with reduced N-3 consumption, yet how N-3 dietary deficiency during perinatal development modulates motivation for palatable food and interacts with a high-fat diet to affect body weight and emotional states is not clear. Pregnant C57Bl6 mice and pups were subjected to diets either deficient or adequate (control) in N-3 until postnatal day 21. Adult male N-3 deficient or control offspring were tested in a progressive ratio operant task for sucrose motivated behavior or given prolonged access to a saturated high-fat diet or chow followed by measures of energy balance and anxiety-like behavior in the elevated-plus maze and open field test. Brain fatty acid profiles were measured via gas chromatography mass spectrometry. Perinatal dietary N-3 deficiency lowered brain N-3 levels, augmented the rewarding effects of sucrose, heightened diet-induced weight gain and fat mass accumulation and diminished spontaneous physical activity. Finally, perinatal N-3 deficiency increased anxiety-like behaviour independent of diet in the open field but not in the elevated-plus maze test. Insufficient dietary N-3 during critical periods of developmental can amplify the obesogenic effects of saturated fat intake, enhance motivated behaviour for palatable foods and may elicit negative emotional states that can perpetuate overeating and obesity.
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Dieta , Ácidos Graxos Ômega-3/deficiência , Obesidade/metabolismo , Recompensa , Sacarose/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/fisiologia , Encéfalo/metabolismo , Ingestão de Alimentos/fisiologia , Ácidos Graxos Ômega-3/metabolismo , Feminino , Camundongos , GravidezRESUMO
α/ß-Hydrolase domain 6 (ABHD6) is a monoacylglycerol hydrolase that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Although complete or peripheral ABHD6 loss of function is protective against diet-induced obesity and insulin resistance, the role of ABHD6 in the central control of energy balance is unknown. Using a viral-mediated knockout approach, targeted endocannabinoid measures, and pharmacology, we discovered that mice lacking ABHD6 from neurons of the ventromedial hypothalamus (VMHKO) have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMHKO mice exhibited blunted fasting-induced feeding and reduced food intake, energy expenditure, and adaptive thermogenesis in response to cold exposure, high-fat feeding, and dieting (transition to a low-fat diet). Our findings identify ABHD6 as a regulator of the counter-regulatory responses to major metabolic shifts, including fasting, nutrient excess, cold, and dieting, thereby highlighting the importance of ABHD6 in the VMH in mediating energy metabolism flexibility.
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Metabolismo Energético , Hipotálamo/metabolismo , Monoacilglicerol Lipases/metabolismo , Animais , Ácidos Araquidônicos/farmacologia , Temperatura Baixa , Dieta Hiperlipídica , Endocanabinoides/farmacologia , Metabolismo Energético/efeitos dos fármacos , Deleção de Genes , Glicerídeos/farmacologia , Hipotálamo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Reprodutibilidade dos Testes , Termogênese/efeitos dos fármacos , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior. METHODS: Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test. RESULTS: GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet. CONCLUSION: Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.
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Ansiedade/prevenção & controle , Ingestão de Alimentos/fisiologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/fisiologia , Recompensa , Animais , Benzofuranos/administração & dosagem , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Condicionamento Operante/fisiologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Infusões Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Atividade Motora/efeitos dos fármacos , Receptores Acoplados a Proteínas G/biossíntese , Sulfonas/administração & dosagem , Sulfonas/farmacologiaRESUMO
Recent studies suggested that the immunometabolic receptors; C5aR and C5L2, constitutively self-associate into homo-/heterodimers and that acylation stimulating protein (ASP/C3adesArg) or C5a treatment of adipocytes increased their colocalization. The present study evaluates the C5aR contribution in adipocytes to the metabolic and immune responses elicited by ligand stimulation. The effects of C5a, ASP, and insulin on cytokine production, triglyceride synthesis (TGS), and key signaling pathways were evaluated in isolated primary adipocytes and cultured 3T3-L1 differentiated adipocytes. In addition, mRNA expression of IRS1 and PGC1α was compared in adipose tissue samples from WT vs. C5aRKO mice. Both C5a and ASP directly increased MCP-1 (238±4%; P<0.001, and 377±2% vs. basal 100%; P<0.001, respectively) and KC (413±11%; P<0.001, and 529±16%; P<0.001 vs. basal 100%, respectively) secretion, TGS (131±1%; P<0.001, and 152±6%; P<0.001, vs. basal 100% respectively), and Akt/NFκB phosphorylation pathways in adipocytes. However, in C5aRKO adipocytes, C5a effects were disrupted, while stimulatory effects of ASP were mostly maintained. Addition of C5a completely blocked ASP signaling and activity in both C5aRKO and WT adipocytes as well as 3T3-L1 adipocytes. Furthermore, C5aRKO adipocytes revealed impaired insulin stimulation of cytokine production, with partial impairment of signaling and TGS stimulation, consistent with decreased IRS1 and PGC1α mRNA expression in adipose tissue. These observations indicate the importance of C5aR in adipose tissue metabolism and immunity, which may be regulated through heterodimerization with C5L2.
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Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Receptores de Quimiocinas/metabolismo , Células 3T3-L1 , Adipócitos/imunologia , Animais , Complemento C3 , Complemento C5a/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Modelos Biológicos , Transdução de Sinais/imunologiaRESUMO
Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system that is involved in energy homeostasis and inflammation. ASP acts on and correlates positively with postprandial fat clearance in healthy subjects. However, in obesity, ASP levels are elevated and correlate inversely with fat clearance, indicative of a potential resistance to ASP. Using a mouse model, we hypothesized that, over time, diet-induced obesity (DIO) would result in development of ASP insensitivity, as compared to chow-fed animals as controls. Injection of recombinant ASP in DIO mice failed to accelerate fat clearance to the same extent as in chow-fed mice. DIO mice exhibited higher basal levels of plasma ASP and, after 30weeks of diet, showed lower ASP receptor (C5L2) expression in adipose tissue compared to chow-fed mice. Additionally, ex vivo ASP stimulation failed to induce normal Ser(473)AKT phosphorylation in adipose tissue from DIO mice VS chow-fed controls. These results demonstrate for the first time a state of diet-induced ASP resistance. Changes in the ASP-C5L2 pathway dynamics in obesity could alter the development of obesity and co-morbidities such as atherosclerosis and type 2 diabetes.
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Complemento C3a/administração & dosagem , Complemento C3a/metabolismo , Dieta/efeitos adversos , Obesidade/etiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Ração Animal , Animais , Complemento C3a/fisiologia , Complemento C5a/biossíntese , Gorduras na Dieta/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Distribuição Aleatória , Sensibilidade e EspecificidadeRESUMO
Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which stimulates fat storage and is typically increased in obesity, type 2 diabetes, and cardiovascular disease. Using a diet-induced obesity (DIO) mouse model, the acute effects of ASP on energy metabolism and inflammatory processes in vivo were evaluated. We hypothesized that ASP would specifically exert proinflammatory effects. C57Bl/6 wild-type mice were put on a high-fat-high-sucrose diet for 12 weeks. Mice were then subjected to both glucose and insulin tolerance tests, each manipulation being preceded by recombinant ASP or vehicle (control) bolus injection. ASP supplementation increased whole-body glucose excursion, and this was accomplished with reduced concomitant insulin levels. However, ASP did not directly alter insulin sensitivity. ASP supplementation induced a proinflammatory phenotype, with higher levels of cytokines including IL-6 and TNF-α in plasma and in adipose tissue, liver, and skeletal muscle mRNA. Additionally, ASP increased M1 macrophage content of these tissues. ASP exerted a direct concentration-dependent role in the migration and M1 activation of cultured macrophages. Altogether, the in vivo and in vitro experiments demonstrate that ASP plays a role in both energy metabolism and inflammation, with paradoxical whole-body glucose-sensitizing yet proinflammatory effects.
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Complemento C3a/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Humanos , Insulina/farmacologia , Resistência à Insulina/fisiologia , Interleucina-6/sangue , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Obesity is considered as a systemic chronic low grade inflammation characterized by increased serum pro-inflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7-transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity. AIM: We evaluated the impact of C5L2 on macrophage infiltration in WAT of wildtype (Ctl) and C5L2 knock-out (C5L2(-/-)) mice over 6, 12 and 24 weeks on a chow diet and moderate diet-induced obesity (DIO) conditions. RESULTS: In Ctl mice, WAT C5L2 and C5a receptor mRNA increased (up to 10-fold) both over time and with DIO. By contrast, in C5L2(-/-), there was no change in C5aR in WAT. C5L2(-/-) mice displayed higher macrophage content in WAT, varying by time, fat depot and diet, associated with altered systemic and WAT cytokine patterns compared to Ctl mice. However, in all cases, the M1 (pro-) vs M2 (anti-inflammatory) macrophage proportion was unchanged but C5L2(-/-) adipose tissue secretome appeared to be more chemoattractant. Moreover, C5L2(-/-) mice have increased food intake, increased WAT, and altered WAT lipid gene expression, which is reflected systemically. Furthermore, C5L2(-/-) mice have altered glucose/insulin metabolism, adiponectin and insulin signalling gene expression in WAT, which could contribute to development of insulin resistance. CONCLUSION: Disruption of C5L2 increases macrophage presence in WAT, contributing to obesity-associated pathologies, and further supports a dual role of complement in WAT. Understanding this effect of the complement system pathway could contribute to targeting treatment of obesity and its comorbidities.
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Gordura Intra-Abdominal/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Receptores de Quimiocinas/deficiência , Adipocinas/metabolismo , Animais , Peso Corporal , Células Cultivadas , Fatores Quimiotáticos/metabolismo , Proteínas do Sistema Complemento/metabolismo , Citocinas/sangue , Ingestão de Energia , Feminino , Expressão Gênica , Glucose/metabolismo , Mediadores da Inflamação/sangue , Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/patologia , Gordura Intra-Abdominal/fisiopatologia , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Obesidade/patologia , Obesidade/fisiopatologia , Receptor da Anafilatoxina C5a , Receptores de Formil Peptídeo/metabolismoRESUMO
OBJECTIVE: To investigate the impact of whole body C5a receptor (C5aR) deficiency on energy metabolism and fat storage. DESIGN: Male wildtype (WT) and C5aR knockout (C5aRKO) mice were fed a low fat (CHOW) or a high fat high sucrose diet-induced obesity (DIO) diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR. RESULTS: At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO) as well as smaller gonadal (-38% CHOW, -36% DIO) and inguinal (-29% CHOW, -30% DIO) fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW) and liver (CHOW and DIO) and PPARγ was increased in muscle and liver. CONCLUSION: These observations point towards a role (either direct or indirect) for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.
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Tecido Adiposo/metabolismo , Metabolismo Energético , Receptor da Anafilatoxina C5a/deficiência , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Homeostase , Insulina/metabolismo , Resistência à Insulina , Fígado/citologia , Fígado/metabolismo , Masculino , Camundongos , Atividade Motora , Músculos/citologia , Músculos/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Oxigênio/metabolismo , Receptor da Anafilatoxina C5a/genética , Receptores de Quimiocinas/genéticaRESUMO
INTRODUCTION: Acylation stimulating protein (ASP) is a hormone secreted by the adipose tissue that has been shown to increase triglyceride storage and glucose transport in adipocytes. These effects are mediated by C5L2 receptor, which has also been associated with inflammatory effects. C5L2 deficient mice on a low-fat diet are hyperphagic yet lean due to increased energy expenditure. The present study assessed insulin sensitivity and metabolic and inflammatory changes in C5L2KO mice vs WT in diet-induced obesity. METHODS: We placed C5L2KO and WT mice on a diabetogenic diet for 12 weeks and examined in vivo and ex vivo metabolism. RESULTS: C5L2KO mice on a diabetogenic diet exhibit decreased insulin sensitivity. Whole body substrate partitioning is evidenced through increased glucose uptake by the liver and decreased uptake by adipose tissue and skeletal muscle. Lipid content of both liver and skeletal muscle was higher in C5L2KO mice vs WT. Furthermore, elevated levels of macrophage markers were found in adipose tissue, liver and skeletal muscle of C5L2KO mice vs WT. Several inflammatory cytokines such as IL-6, MIP-1α and KC were also elevated in plasma of C5L2KO mice vs WT. CONCLUSIONS: Overall, we demonstrated that C5L2KO mice fed a diabetogenic diet develop more severe insulin resistance than WT mice through altered substrate partitioning, ectopic fat deposition and a pro-inflammatory phenotype.
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Tecido Adiposo/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Receptores de Quimiocinas/metabolismo , Tecido Adiposo/imunologia , Animais , Distribuição da Gordura Corporal , Células Cultivadas , Complemento C3 , Citocinas/genética , Citocinas/metabolismo , Dieta/efeitos adversos , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/imunologia , Obesidade/etiologia , Obesidade/genética , Obesidade/imunologia , Receptor da Anafilatoxina C5a , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Triglicerídeos/genética , Triglicerídeos/metabolismoRESUMO
CONTEXT: An exaggerated inflammatory response in patients undergoing major liver resection coupled with poor nutrition diminishes liver regenerative capacity and increases the risk of postoperative complications. OBJECTIVES: Our objective was to evaluate the biological context leading to better clinical outcomes in patients undergoing liver resection coupled with hyperinsulinemic-normoglycemic clamp vs. standard care (insulin sliding care). DESIGN AND SETTING: This study was a fundamental research analysis of a patient subset from a randomized-controlled study at the McGill University Health Center. PATIENTS AND INTERVENTION: Thirty consenting patients participating in a randomized clinical trial for liver resection received either hyperinsulinemic-normoglycemic clamp technique with 24-h preoperative carbohydrate load (intervention) or standard glucose control through insulin sliding scale treatment (control). MAIN OUTCOME MEASURES: Liver biopsies and plasma samples were taken at various time points before and after surgery. Primary measures included mRNA quantitation for genes related to insulin signaling, inflammation, and proliferation; proinflammatory cytokines at various time points; and liver function markers. These measurements were associated with clinical outcomes. RESULTS: The hyperinsulinemic-normoglycemic clamp technique reduced postoperative liver dysfunction, infections, and complications. Markers of energy stores indicated higher substrate availability. Cytokine expression pattern was altered (TNF-α, IL-8, monocyte chemoattractant protein-1, IL-6, IL-10, and C-reactive protein). Apoptosis was markedly reduced, whereas the complement system was unaltered. CONCLUSION: The hyperinsulinemic-normoglycemic clamp technique reduced postoperative negative outcomes by suppressing apoptosis. This phenomenon appears to be linked with higher substrate availability and altered cytokine secretion profile and may provide a long-term benefit of this therapy on liver resection patients.
Assuntos
Apoptose/efeitos dos fármacos , Inflamação/prevenção & controle , Insulina/administração & dosagem , Hepatopatias/prevenção & controle , Fígado/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Idoso , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Técnica Clamp de Glucose , Hepatectomia/efeitos adversos , Hepatite/etiologia , Hepatite/patologia , Hepatite/prevenção & controle , Humanos , Inflamação/patologia , Insulina/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Hepatopatias/etiologia , Masculino , Pessoa de Meia-Idade , Padrão de CuidadoRESUMO
BACKGROUND: Acylation stimulating protein (ASP) is an adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes. Previous studies have shown that ASP-deficient C3 knockout mice are hyperphagic yet lean, as they display increased oxygen consumption and fatty acid oxidation compared to wildtype mice. In the present study, antibodies against ASP (Anti-ASP) and human recombinant ASP (rASP) were tested in vitro and in vivo. Continuous administration for 4 weeks via osmotic mini-pump of Anti-ASP or rASP was evaluated in wildtype mice on a high-fat diet (HFD) to examine their effects on body weight, food intake and energy expenditure. RESULTS: In mature murine adipocytes, rASP significantly stimulated fatty acid uptake (+243% vs PBS, P < 0.05) while Anti-ASP neutralized the rASP response. Mice treated with Anti-ASP showed elevated energy expenditure (P < 0.0001), increased skeletal muscle glucose oxidation (+141%, P < 0.001), reduced liver glycogen (-34%, P < 0.05) and glucose-6-phosphate content (-64%, P = 0.08) compared to control mice. There was no change in body weight, food intake, fasting insulin, adiponectin, CRP or TG levels compared to controls. Interestingly, HFD mice treated with rASP showed the opposite phenotype with reduced energy expenditure (P < 0.0001) and increased body weight (P < 0.05), cumulative food intake (P < 0.0001) and liver glycogen content (+59%, P < 0.05). Again, there was no change in circulating insulin, adiponectin, CRP or TG levels, however, plasma free fatty acids were reduced (-48%, P < 0.05). CONCLUSION: In vitro, Anti-ASP effectively neutralized ASP stimulated fatty acid uptake. In vivo, Anti-ASP treatment increased whole body energy utilization while rASP increased energy storage. Therefore, ASP is a potent anabolic hormone that may also be a mediator of energy expenditure.
Assuntos
Adipócitos/metabolismo , Anticorpos Neutralizantes/farmacologia , Metabolismo Energético/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Células 3T3-L1 , Acilação/fisiologia , Adipócitos/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Calorimetria Indireta , Complemento C3 , Gorduras na Dieta/farmacocinética , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/farmacocinética , Hormônios/sangue , Humanos , Bombas de Infusão , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Proteínas Recombinantes/farmacologiaRESUMO
ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (-39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (-25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (-31%, P = 0.005), hexokinase (-43%, P = 0.007), phosphofructokinase (-51%, P < 0.0001), and GAPDH (-15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (-48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.