Sustained Intracerebroventricular Infusion of Brain Fuels Reduces Body Weight and Food Intake in Rats

Davis, John D.; Wirtshafter, David; Asin, Karen E.; Brief, Deborah J.

doi:10.1126/science.7193909

Cited by 145 publications

(64 citation statements)

References 22 publications

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“…The observation that rodents on nonketotic, high-fat diets gain weight faster than those on ketotic, high-fat diets supports this idea (22,24,25). Furthermore, exogenously administered ␤HB causes weight loss (26). Despite these observations, our results suggest that ketosis alone cannot slow weight gain because the KD caused ketosis in ob/ob and db/db mice without slowing weight gain.…”

Section: Discussioncontrasting

confidence: 49%

Leptin Contributes to Slower Weight Gain in Juvenile Rodents on a Ketogenic Diet

et al. 2006

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ABSTRACT:The ketogenic diet (KD) is an efficacious therapy for medically refractory childhood epilepsy that also slows weight gain. We tested the hypothesis that the KD slows weight gain via neurohormones involved in energy homeostasis. We found that juvenile rodents fed a KD had slower weight gain than those fed a standard diet (SD). Rats fed a KD had higher serum leptin levels and lower insulin levels compared with those fed an SD. We investigated the increase in leptin further because this change was the only one consistent with slower weight gain. Although rats fed the SD experienced slower weight gain when calorie restricted, they had serum leptin levels similar to those fed the SD ad libitum. Furthermore, leptin deficient (ob/ob) and leptin receptor deficient (db/db) mice did not show slower weight gain on the KD. All animals on the KD had elevated serum ␤-hydroxybutyrate (␤HB) levels. Thus, ketosis is insufficient and a functioning leptin signaling system appears necessary for the KD to slow weight gain. The increase in leptin may contribute to the anticonvulsant effects of the KD. F ew treatment options exist for the 20 -30% of epileptic children whose seizures are refractory to medication. One option is the KD, a high-fat, low-carbohydrate, and adequate protein diet. The KD is remarkably effective in children with medically refractory epilepsy as 5-10% become seizure free and 30% have a Ͼ90% reduction in seizure frequency (1). Yet, its adverse effects and the parental effort involved in implementing and maintaining the diet limit its use. Thus, all epileptic children would benefit from a simpler method of attaining the diet's anticonvulsant effects, which requires elucidating its mechanism of action.Here we focus on what the impaired weight gain associated with the KD might reveal about the diet's anticonvulsant mechanism. Several studies report that children on the KD drop about 10 percentiles in weight, although appropriate weight gain is the goal (2,3). Recognizing that lowcarbohydrate diets, such as the Atkins diet, are ketogenic makes this impaired weight gain less surprising. Indeed, the Atkins diet and other low-carbohydrate KDs result in a 5% to 10% weight loss over 6 mo (4,5). Furthermore, rodents placed on a KD show slower weight gain (6,7).We hypothesized that the anticonvulsant and weight effects of the KD share a common mechanism involving a change in the serum levels of leptin, insulin, ghrelin, or cortisol. These peripherally released hormones help determine body weight because they regulate energy homeostasis (8). Importantly, leptin and insulin also modulate neuronal excitability (9,10). METHODSDietary protocols. Experimental protocols were approved by the Washington University Animal Studies Committee. Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), male ob/ob mice (Stock 000632, The Jackson Laboratory, Bar Harbor, ME), male C57BL/6J mice (Stock 000664, The Jackson Laboratory), male db/db mice (Stock 000642, The Jackson Laboratory), and male C57BLKS/J mice (Stock 0006...

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Section: Discussioncontrasting

confidence: 49%

Leptin Contributes to Slower Weight Gain in Juvenile Rodents on a Ketogenic Diet

et al. 2006

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“…However, before we can exclude the differences in corticosterone as contributing to the differences in peptide expression, studies examining the effect of diabetes and diet on circadian patterning of the hypothalamic-pituitary-adrenal axis are required. Nonetheless, our data and others (7,32) raise the possibility of a dissociation between levels of plasma corticosterone and of PVN CRH gene expression. Specifically, the preservation of elevated corticosterone levels despite reduced CRH mRNA levels in the HC group of diabetic rats suggests the possibility that corticosterone elevation occurred via factors in addition to, or separate from, CRH.…”

Section: Discussionmentioning

confidence: 77%

Effect of a high-fat diet on food intake and hypothalamic neuropeptide gene expression in streptozotocin diabetes.

Chavez¹,

Seeley²,

Havel³

et al. 1998

J. Clin. Invest.

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Insulin-deficient diabetic rats are markedly hyperphagic when fed a high-carbohydrate (HC) diet, but normophagic when fed a high-fat (HF) diet. When maintained on a HC diet, diabetic rats also exhibit increased gene expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, and reduced expression of the anorectic peptide corticotropin-releasing hormone (CRH) in the paraventricular nucleus, and these changes are hypothesized to contribute to diabetic hyperphagia. In this experiment we assessed whether the normophagia displayed by HF-fed diabetic rats is associated with the opposite profile of NPY and CRH expression. Our results show that relative to diabetic rats on the HC diet, the diabetic rats on the HF diet exhibited significantly reduced caloric intake ( Ϫ 40%), NPY expression in the arcuate nucleus ( Ϫ 27%), and elevated CRH expression in the paraventricular nucleus ( ϩ 37%). Insulin and corticosterone, which are known to affect hypothalamic NPY and CRH expression, were not different between these two groups, making it unlikely that they can account for the differences in either feeding behavior or hypothalamic peptide expression. There was a small but significant increase in plasma leptin levels in the diabetic animals maintained on the HF, and large differences in parameters associated with elevated fat oxidation. These observations support the hypothesis that the normalization of food intake observed in diabetic rats consuming a HF diet may in part be mediated

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“…High brain glucose concentrations suppress food intake and body mass consistent with a negative feedback regulation. 4,5 Pathways that allocate glucose into the brain, thereby increasing brain glucose feedback, should indirectly suppress food intake. 3 Vascular endothelial growth factor and sympathoadrenal activity may jointly contribute to such glucose allocation.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Increased brain glucose concentration is known to suppress food intake and thereby decrease body mass via action on hypothalamic regulation centers. 4,5 Blood glucose must be transported by carrier mechanisms across the blood-brain barrier (BBB) to become available for brain metabolism. The carrier protein specific for glucose transport across the BBB is the glucose transporter (GLUT) 1.…”

Section: Introductionmentioning

confidence: 99%

High plasma VEGF relates to low carbohydrate intake in patients with type 2 diabetes

et al. 2006

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Objective: Vascular endothelial growth factor (VEGF) has been suggested to enhance glucose transport across the blood-brain barrier, thereby increasing brain glucose supply. Increased brain glucose concentration is known to suppress food intake and to decrease body mass via action on hypothalamic regulation centers. Based on the crucial role of VEGF on brain glucose supply, we hypothesized that higher VEGF concentrations are associated with lower food intake and body mass in humans. Methods: Intending to investigate subjects with high variance of blood glucose, we examined patients with type 2 diabetes mellitus. Our hypothesis was tested in a population-based cohort of 190 subjects with type 2 diabetes. Plasma VEGF levels in conjunction with other parameters known to modulate food intake were measured and subsequently correlated with food intake patterns at a breakfast buffet as well as with body mass. Results: We found that subjects with higher concentrations of plasma VEGF had 17% less carbohydrate intake (P ¼ 0.003) and 4.8% lower body mass (P ¼ 0.017) than those with lower VEGF concentrations. Intake of protein and fat did not correlate with VEGF concentrations. These associations of plasma VEGF were confirmed in multiple linear regression analyses controlling for several parameters interacting with food intake. Conclusion: We conclude that high plasma VEGF concentrations are associated with less carbohydrate intake and lower body mass in type 2 diabetes. The role VEGF plays in facilitating glucose access to the brain represents a new aspect of food intake regulation and energy homeostasis, with relevance for diseases with body mass disturbances.

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Sustained Intracerebroventricular Infusion of Brain Fuels Reduces Body Weight and Food Intake in Rats

Cited by 145 publications

References 22 publications

Leptin Contributes to Slower Weight Gain in Juvenile Rodents on a Ketogenic Diet

Leptin Contributes to Slower Weight Gain in Juvenile Rodents on a Ketogenic Diet

Effect of a high-fat diet on food intake and hypothalamic neuropeptide gene expression in streptozotocin diabetes.

High plasma VEGF relates to low carbohydrate intake in patients with type 2 diabetes

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