Recent studies have demonstrated that the rat adipose tissue expresses some of the components necessary for the production of angiotensin II (Ang II) and the receptors mediating its actions. The aim of this work is to characterize the expression of the renin-angiotensin system (RAS) components in perivascular adipose tissue and to assess differences in the expression pattern depending on the vascular bed and type of adipose tissue. We analyzed Ang I and Ang II levels as well as mRNA levels of RAS components by a quantitative RT-PCR method in periaortic (PAT) and mesenteric adipose tissue (MAT) of 3-month-old male Wistar-Kyoto rats. PAT was identified as brown adipose tissue expressing uncoupling protein-1 (UCP-1). It had smaller adipocytes than those from MAT, which was identified as white adipose tissue. All RAS components, except renin, were detected in both PAT and MAT. Levels of expression of angiotensinogen, Ang-converting enzyme (ACE), and ACE2 were similar between PAT and MAT. Renin receptor expression was five times higher, whereas expression of chymase, AT 1a , and AT 2 receptors were significantly lower in PAT compared with MAT respectively. In addition, three isoforms of the AT 1a receptor were found in perivascular adipose tissue. The AT 1b receptor was found at very a low expression level. Ang II levels were higher in MAT with no differences between tissues in Ang I. The results show that the RAS is differentially expressed in white and brown perivascular adipose tissues implicating a different role for the system depending on the vascular bed and the type of adipose tissue.

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Valladolid-Acebes I, Merino B, Principato A, Fole A, Barbas C, Lorenzo MP, García A, Del Olmo N, Ruiz-Gayo M, Cano V. High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission. Am J Physiol Endocrinol Metab 302: E396 -E402, 2012. First published November 22, 2011; doi:10.1152/ajpendo.00343.2011.-Obesity and high-fat (HF) diets have a deleterious impact on hippocampal function and lead to impaired synaptic plasticity and learning deficits. Because all of these processes need an adequate glutamatergic transmission, we have hypothesized that nutritional imbalance triggered by these diets might eventually concern glutamate (Glu) neural pathways within the hippocampus. Glu is withdrawn from excitatory synapses by specific uptake mechanisms involving neuronal (EAAT-3) and glial (GLT-1, GLAST) transporters, which regulate the time that synaptically released Glu remains in the extracellular space and, consequently, the duration and location of postsynaptic receptor activation. The goal of the present study was to evaluate in mouse hippocampus the effect of a short-term high-fat dietary treatment on 1) Glu uptake kinetics, 2) the density of Glu carriers and Glu-degrading enzymes, 3) the density of Glu receptor subunits, and 4) synaptic transmission and plasticity. Here, we show that HF diet triggers a 50% decrease of the Michaelis-Menten constant together with a 300% increase of the maximal velocity of the uptake process. Glial Glu carriers GLT-1 and GLAST were upregulated in HF mice (32 and 27%, respectively), whereas Glu-degrading enzymes glutamine synthase and GABA-decarboxilase appeared to be downregulated in these animals. In addition, HF diet hippocampus displayed diminished basal synaptic transmission and hindered NMDAinduced long-term depression (NMDA-LTD). This was coincident with a reduced density of the NR2B subunit of NMDA receptors. All of these results are compatible with the development of leptin resistance within the hippocampus. Our data show that HF diets upregulate mechanisms involved in Glu clearance and simultaneously impair Glu metabolism. Neurochemical changes occur concomitantly with impaired basal synaptic transmission and reduced NMDA-LTD. Taken together, our results suggest that HF diets trigger neurochemical changes, leading to a desensitization of NMDA receptors within the hippocampus, which might account for cognitive deficits. obesity; electrophysiology; learning; long-term depression; glutamate uptake; leptin resistance GLUTAMATE (Glu) uptake is a pivotal process regulating excitatory transmission within the central nervous system, and its efficacy accounts for the time that released Glu remains in the extracellular space and, consequently, the duration of postsynaptic receptor activation. Glu uptake is carried out by specific neuronal (EAAT-3) and glial (GLT-1, GLAST) transporters, which display dynamic processes aimed at improving Glu clearance under conditions leading to increased release of Glu (27, 34). Impairment of Glu uptake due to brain injury (24, 28...

The objective of this work was to characterize the adaptation of cardiac metabolism to a lipid overload in a model of diet-induced obesity (DIO) in mice. After 8 wk dietary treatment, mice receiving a high-fat diet exhibited an increase in the amount of adipose tissue, accompanied by a surge in plasma leptin concentration (from 5.4-16.0 ng/ml). This was associated with: 1) an induction of uncoupling protein-2 (120%), 2) an increase in the phosphorylated form of AMP-activated protein kinase (120%), and 3) a reduction in lactate concentration and lactate dehydrogenase activity in myocardial tissue (40%). Because DIO induces leptin resistance, we analyzed leptin receptor functionality by measuring phospho-signal transducer and activator of transcription 3 in response to acute leptin (1 mg/kg). We observed that leptin receptor signaling remained unaltered within the heart but was fully impaired within the hypothalamus. Taken together, these data show that during DIO development, there is a metabolic shift in the heart aimed at increasing fatty acid oxidation to the detriment of carbohydrates. This effect seems to be leptin-dependent, suggesting that the increased adiposity observed during the onset of obesity might contribute to impairing ectopic lipidic deposition in the heart.

Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control.