Is Dog Owner Obesity a Risk Factor for Canine Obesity? A "One-Health" Study on Human-Animal Interaction in a Region with a High Prevalence of Obesity.

Obesity in humans is a growing global problem and is one of the greatest public health challenges we face today. Most researchers agree that, as in humans, the incidence in the companion animal population is also increasing. The aim of this study was to evaluate the risk factors contributing to canine obesity in a region with a high rate of human obesity (Canary Islands, Spain), co-occurrence of obesogenic risk factors, and a canine population with a high percentage of unneutered dogs. We have focused on owner risk factors that promote obesity in humans, such as weight, lifestyle, nutritional habits, and low physical activity, among others. Thus, the human-animal interaction relationship that contributes to human obesity and influences canine obesity has been studied. A multicentre cross-sectional analytical study of 198 pairs of dogs from urban households and their owners was used. A multivariable logistic regression study was completed to analyse owner characteristics variables associated with canine obesity. This transdisciplinary study was conducted with physicians and veterinarians using a "One Health" approach. Our results suggest that, in a region of high obesogenic risk, obese/overweight dogs are primarily female, older than 6 years, and neutered. Being an overweight dog owner was found to be the most important factor in the occurrence of obesity in dogs. Owners of overweight dogs were mainly females, older than 40 years, who did not engage in any physical activity. A strong correlation has been found between dog owners with low levels of education and obesity in their dogs. We suggest that veterinarians should develop and design strategies to encourage pet owners to engage in physical activity with their dogs for the benefit of both.

Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection.

Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P<0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARgamma transcriptional activity in neurons and astrocytes (122.1%+/-8.1% and 158.6%+/-22.6% of control PPARgamma transcriptional activity, n=6, P<0.05). Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.

TNF-alpha converting enzyme (TACE) protein expression in different clinical subtypes of multiple sclerosis.

Tumor necrosis factor (TNF)-alpha converting enzyme (TACE, also called ADAM17) is a key sheddase that releases TNF-alpha from its inactive cell-bound precursor. TACE protein expression levels in peripheral blood mononuclear cells were measured by Western blot analysis in 20 healthy controls and 80 multiple sclerosis (MS) patients before and after treatment with IFNbeta [20 patients with primary progressive (PP) MS, 20 patients with secondary progressive (SP) MS, and 40 patients with relapsing- remitting (RR) MS (20 patients during clinical remission and 20 patients in relapse)]. TNF-alpha serum levels were also measured by enzyme-linked immunoassay in the MS patients and healthy controls. TACE protein expression levels were lower in healthy controls and PPMS patients compared with SPMS patients and RRMS patient during clinical remission. No differences in TACE protein levels were observed between RRMS patients in relapse and during remission. TACE protein levels were increased in PPMS patients treated with IFNbeta. Serum TNF-alpha levels were higher in RRMS patients in relapse compared with RRMS patients during remission, and positive and negative correlations were found between TACE protein expression and serum TNF-alpha levels in RRMS patients during relapse and during remission respectively. These findings point to different regulatory mechanisms of the TACE-TNF-alpha pathway in the clinical MS subtypes and expand the role of TACE in MS pathogenesis.

In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-alpha pathway.

A short ischemic event [ischemic preconditioning (IPC)] can result in a subsequent resistance to severe ischemic injury (ischemic tolerance). Although tumor necrosis factor-alpha (TNF-alpha) contributes to the brain damage found after cerebral ischemia, its expression and neuroprotective role in models of IPC have also been described. Regarding the role of TNF-alpha convertase (TACE/ADAM17), we have recently shown its upregulation in rat brain after IPC induced by transient middle cerebral artery occlusion and that subsequent TNF-alpha release accounts for at least part of the neuroprotection found in this model. We have now used an in vitro model of IPC using rat cortical cultures exposed to sublethal oxygen-glucose deprivation (OGD) to investigate TACE expression and activity after IPC and the subsequent mechanisms of ischemic tolerance. OGD-induced cell death was significantly reduced in cells exposed to IPC by sublethal OGD 24 hr before, an effect that was inhibited by the TACE inhibitor BB3103 (1 microm) and anti-TNF-alpha antibody (2 microg/ml) and that was mimicked by TNF-alpha (10 pg/ml) preincubation. Western blot analysis showed that TACE expression is increased after IPC. IPC caused TNF-alpha release, an effect that was blocked by the selective TACE inhibitor BB-3103. In addition, IPC diminished the increase in extracellular glutamate caused by OGD and increased cellular glutamate uptake and expression of EAAT2 and EAAT3 glutamate transporters; however, only EAAT3 upregulation was mediated by increased TNF-alpha. These data demonstrate that neuroprotection induced by IPC involves upregulation of glutamate uptake partly mediated by TACE overexpression.

TNFR1 upregulation mediates tolerance after brain ischemic preconditioning.

A short ischemic event (ischemic preconditioning (IPC)) can result in subsequent resistance to severe ischemic injury (ischemic tolerance (IT)). The expression and neuroprotective role of tumor necrosis factor (TNF-alpha) have been described in models of IPC and we have showed the participation of its processing enzyme, the TNF-alpha convertase enzyme (TACE) in this process. We have now decided to explore the expression and localization of TNF receptors (TNFR) as well as other signalling mechanisms involved in IT. A period of 10 mins of temporary middle cerebral artery occlusion (tMCAO) was used for focal IPC. To evaluate the ability of IPC to produce IT, permanent MCAO was performed 48 hours after IPC. Ischemic preconditioning produced a reduction in infarct volume, as we showed previously. Ischemic preconditioning caused upregulation of neuronal TNFR1 that was reduced by the selective TACE inhibitor BB1101. Intracerebral administration of TNFR1 antisense oligodeoxynucleotide, which caused a reduction in TNFR1 expression, inhibited the IPC-induced protective effect, showing that TNFR1 upregulation is implicated in IT. Moreover, treatment with BB1101, TNFR1 antisense and lactacystin-a specific proteasome inhibitor-blocked IPC-induced NF-kappaB. Immunohistochemical studies showed the expression of TACE and TNFR1 in neurons. In summary, these data show that IPC produces neuronal upregulation of TACE and TNFR1, and that the pathway TACE/TNF-alpha/TNFR1/NF-kappaB is involved in IT.

Expression and function of tumour necrosis factor-alpha-converting enzyme in the central nervous system.

Tumour necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE/ADAM17) is a membrane protein belonging to the ADAM (a disintegrin and a metalloprotease) family able to cleave various membrane proteins, including the transmembrane form of TNF-alpha at its physiological processing site. Being an ADAM, TACE may mediate not only proteolysis but also adhesive interactions; however, the role of the disintegrin domain of TACE has not been studied. In the central nervous system (CNS), little is known about the physiological role of TACE, but some important pathophysiological functions have been reported recently, with both neurotoxic and neuroprotective repercussions. This article discusses and reviews the main contributions to this field of investigation addressing the expression and function of TACE in the CNS.