RESUMO
AIMS: Investigate the involvement of the histaminergic projections from tuberomammillary nucleus (TMN) to the spinal cord in the modulation of nociception and peripheral edema in a model of monoarthritis. MAIN METHODS: Subacute monoarthritis was induced by an intraarticular injection of carrageenan followed by LPS 72 h later. Disability and joint edema were assessed at the 3rd hour after LPS and at every hour up to 6 h. KEY FINDINGS: Intrathecal administration of histamine potentiated joint incapacitation and edema, while the H1R antagonist cetirizine decreased both. The H3R agonist immepip decreased both incapacitation and edema, while the H3R antagonist thioperamide had the opposite effect. The microinjection of glutamate into the ventral TMN (vTMN) caused an increase of incapacitation and articular edema, whereas the blockade of this nucleus by cobalt chloride inhibited both parameters. Intrathecal administration of cetirizine prevented the increase of incapacitation and joint edema caused by glutamate microinjection into the vTMN. Similarly, an intrathecal injection of the NKCC1 cotransporter inhibitor bumetanide prevented the effects of glutamate microinjection into the vTMN, whereas coadministration of histamine with bumetanide only inhibited the potentiation of joint edema. A microinjection of orexin B into the vTMN potentiated incapacitation and joint edema, while coadministration of the OX1/2 receptor antagonist almorexant with orexin B did not. SIGNIFICANCE: These data support the notion that TMN participates in the modulation of a peripheral inflammatory process by means of histaminergic projections to the spinal cord, and the hypothalamus may trigger TMN activation by means of glutamate and orexin.
Assuntos
Artrite Experimental/fisiopatologia , Edema/patologia , Região Hipotalâmica Lateral/metabolismo , Nociceptividade/fisiologia , Medula Espinal/metabolismo , Acetamidas/farmacologia , Animais , Feminino , Histamina/administração & dosagem , Isoquinolinas/farmacologia , Orexinas/administração & dosagem , Ratos , Ratos WistarRESUMO
Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from â¼ 35 to â¼ 1,450 pmol/L). The insulin-induced UPR was not due to increased glucose uptake/metabolism and oxidative stress. It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and with multiple posttranslational protein modifications (acetylations, methylations, nitrosylations, succinylation, and ubiquitinations), some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative mechanism for the development of ER stress in obesity. They may also have clinical and therapeutic implications, e.g., in diabetic patients treated with high doses of insulin.
Assuntos
Tecido Adiposo/metabolismo , Insulina/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Células 3T3-L1 , Adulto , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Glucose/metabolismo , Humanos , Insulina/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Ubiquitinação , Resposta a Proteínas não Dobradas/genéticaRESUMO
The fermentation of pectin by colonic bacteria produces short-chain fatty acids (SCFA) which are then absorbed by the host. The purpose of this study was to determine whether pectin, added to a chemically defined diet, would increase hepatic lipogenesis and whether this effect is mediated by intestinal bacteria. Eighteen Sprague-Dawley rats underwent placement of a feeding gastrostomy and a swivel apparatus. Postoperatively, rats were randomly assigned to one of three groups: 1) No Pectin received a fat-free chemically defined diet, 2) Pectin received the same diet with the addition of 1% (w/v) pectin, and 3) Neomycin received the same diet with 1% w/v pectin and neomycin (80 mg/kg of body weight daily). On the 5th postoperative d, all diets included 12.5% (v/v) deuterium as D2O. After the infusion of the labeled diets for 24 hr, the content and deuterium enrichment of liver palmitate, stearate and oleate were measured and the production rates calculated. The liver content and production rates of these fatty acids were higher in Pectin animals than in either the No Pectin or Neomycin animals. Since the effect of pectin on hepatic lipogenesis was reduced by the concomitant administration of the intestinal antibiotic neomycin, it appears that this effect depends on the bacterial fermentation of pectin. It is postulated that the SCFA produced during pectin fermentation promote lipogenesis via a direct stimulatory effect, in addition to being carbon donors.
Assuntos
Lipídeos/biossíntese , Fígado/metabolismo , Pectinas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta , Ácidos Graxos/análise , Mucosa Intestinal/metabolismo , Fígado/efeitos dos fármacos , Masculino , Nitrogênio/análise , Tamanho do Órgão/efeitos dos fármacos , Pectinas/administração & dosagem , Ratos , Ratos EndogâmicosRESUMO
The energy expenditure of lower (group 1) and upper socioeconomic group females (group 2) from a marginal community in Guatemala City was determined by using the doubly labelled water method. Energy expenditure values were 1925 +/- 66 (mean, SEM) kcal/d (group 1) and 2253 +/- 145 kcal/d group 2 (p less than 0.03). About half of this difference can be attributed to size.