A second look at the barriers of the medial basal hypothalamus

Peruzzo, Bruno; Pastor, Francisco E.; Blázquez, Juan Luis; Schöbitz, Karin; Peláez, B; Amat, P; Rodríguez, Estéban M.

doi:10.1007/s002219900289

Cited by 232 publications

(171 citation statements)

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“…Several reasons may explain why this central effect was only presented in obese mice, one of which might be the higher permeability of the blood-brain barrier in obese models (including ARC lesion mice and ob/ob mice) when compared with normal models (Skultetyova et al 1998). Several experiments have suggested that blood-brain barriers of obese models, such as ARC lesion mice and ob/ob mice, are more permeable than normal animals, especially under stress conditions (Sharma & Dey 1988, Skultetyova et al 1998, Peruzzo et al 2000. A second explanation for this consequence might be the different effective dosages needed for different species or models, as food intake is regulated according to body size and drug sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732

Kim

Jin

et al. 2007

Journal of Molecular Endocrinology

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The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114 . 8G13 . 4 g vs 170 . 7G20 . 6 g, 7 . 9G0 . 5% decrease vs 0 . 3G2 . 2% decrease; in treated OLETF rat versus control OLETF rat, P!0 . 01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.

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Section: Discussionmentioning

confidence: 99%

Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732

Kim

Jin

et al. 2007

Journal of Molecular Endocrinology

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“…Exactly how the loss of tanycytes and ependymocytes might contribute to glucoprivic deficits is not entirely clear. However, ␣ and ␤1 tanycytes, located in the ventrolateral two-thirds of the 3v, form long processes that contact neurons in the VMN (␣) (39) and ARC (␤1) (43,44), while the proximal portion of tanycytes contact the 3v CSF (39,44). Thus, tanycytes may provide metabolic and/or physical support for adjacent astrocytes and neurons (39).…”

Section: Discussionmentioning

confidence: 99%

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

2004

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Glucokinase (GK) is hypothesized to be the critical glucosensor of pancreatic ␤-cells and hypothalamic glucosensing neurons. To understand the role of GK in glucoprivic counterregulatory responses, we injected alloxan, a GK inhibitor and toxin, into the third ventricle (3v) to target nearby GK-expressing neurons. Four and 6 days after 3v, but not 4v, alloxan injection, alloxan-treated rats ate only 30% and their blood glucose area under the curve was only 28% of saline controls' after systemic 2-deoxy-D-glucose. In addition, their hyperglycemic response to hindbrain glucoprivation induced with 5-thio-glucose was impaired, whereas fasting blood glucose levels and food intake after an overnight fast were elevated. These impaired responses were associated with the destruction of 3v tanycytes, reduced glial fibrillary acidic protein-immunoreactivity surrounding the 3v, neuronal swelling, and decreased arcuate nucleus neuropeptide Y (NPY) mRNA. Nevertheless, hypothalamic GK mRNA was significantly elevated. Two weeks after alloxan injection, 3v tanycyte destruction was reversed along with restoration of feeding and hyperglycemic responses to both systemic and hindbrain glucoprivation. At this time there were significant decreases in GK, NPY, and proopiomelanocortin mRNA. Thus, neural substrates near and around the 3v affected by alloxan may be critically involved in the expression of these glucoprivic responses. Diabetes 53: 1230 -1236, 2004 T he brain relies on a continuous supply of glucose as a primary energy source (1) and has evolved mechanisms that detect decreases in blood glucose levels and elicit autonomic, neuroendocrine, and behavioral counterregulatory responses (CRRs) that prevent and correct glucoprivation. One way in which the brain senses alterations in glucose availability is through specialized glucosensing neurons (2-6). These neurons utilize glucose as a signaling molecule to alter their membrane potential and firing rate, whereas the majority of neurons utilize glucose primarily to fuel their metabolic needs (2,3). As extracellular glucose levels decline, glucose-excited neurons decrease and glucoseinhibited neurons increase their action potential frequency (4,7-11). As is the case with pancreatic ␤-cells, it is hypothesized that the high-K m glycolytic enzyme, glucokinase (GK), is a regulator of neuronal glucosensing within the physiological range (10,(12)(13)(14). GK inhibitors alter calcium flux (10,14) and neuronal firing (12) in ventromedial hypothalamus (VMH) glucosensing neurons, and GK mRNA is expressed in glucosensing neurons in the hypothalamic paraventricular nucleus (PVN), dorsomedial nucleus (DMN), ventromedial nucleus (VMN), and arcuate nucleus (ARC) (15,16). Specifically, GK is coexpressed in both ARC neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons (10). GK immunoreactivity (ir) is also localized in the ependymocytes lining the ventricles (17) and serotonin neurons in the midline medulla (17), where glucoprivic stimuli elicit CRRs (18).In vitro studies suggest that GK...

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“…Moreover, weight gain and insulin resistance from habitual consump-tion of palatable foods decrease insulin and leptin blood-brain barrier (BBB) penetrability (Caro et al, 1996;Kaiyala et al, 2000;Banks, 2003;Banks and Farrell, 2003;Woods et al, 2003) and their CNS effects (Couce et al, 2001;Banks and Farrell, 2003;Lindqvist et al, 2005;Porte et al, 2005), albeit some homeostatic hypothalamic areas lack BBB (Peruzzo et al, 2000;Ganong, 2000). The resultant brain insulin and leptin 'resistance' renders normal satiety signals even more ineffective (Erlanson-Albertsson, 2005;Isganaitis and Lustig, 2005) leading to further impairments in physiologic mechanisms regulating food intake (eg, overeating) and shifting the set point for energy homeostasis towards the development of overweight and obesity (Levine et al, 2003;Erlanson-Albertsson, 2005;Isganaitis and Lustig, 2005).…”

Section: Repetitive Palatable Food Consumption May Dysregulate Homeosmentioning

confidence: 99%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

133

142

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Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

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A second look at the barriers of the medial basal hypothalamus

Cited by 232 publications

References 0 publications

Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732

Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

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