Leptin Resistance in Vagal Afferent Neurons Inhibits Cholecystokinin Signaling and Satiation in Diet Induced Obese Rats

Lartigue, Guillaume de; Serre, Claire B. de La; Espero, Elvis; Lee, Jennifer; Raybould, Helen E.

doi:10.1371/journal.pone.0032967

Cited by 120 publications

(148 citation statements)

References 46 publications

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“…Moreover, recently it has been shown that leptin resistance within vagal afferents reduces the sensitivity to CCK receptormediated effects [22]. Furthermore, the beneficial effects of (pGlu-Gln)-CCK-8 were less obvious in leptin-deficient ob/ob mice than in high-fat-fed mice [7].…”

Section: Discussionmentioning

confidence: 99%

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Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

2013

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Aims/hypothesis Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively. Methods The actions and overall therapeutic use of (pGluGln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice. Results (pGlu-Gln)-CCK-8 had prominent (p<0.01 to p< 0.001), acute feeding-suppressive effects, which were significantly augmented (p<0.05 to p<0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p<0.05 to p<0.001), energy intake (p<0.01), circulating triacylglycerol (p<0.01), nonfasting glucose (p<0.05 to p<0.001) and triacylglycerol deposition in liver and adipose tissue (p<0.001). All treatment regimens improved glucose tolerance (p<0.05 to p<0.001) and insulin sensitivity (p<0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p<0.001) energy expenditure. Conclusions/interpretationThese studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

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Section: Discussionmentioning

confidence: 99%

“…Thus, leptin and CCK may potentiate their own effects by cross-stimulating their secretion. Furthermore, leptin has recently been shown to play a role in modulating the sensitivity of vagal afferents to CCK [22].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

2013

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“…Egr1 has been observed to stimulate CART expression in certain types of neurons (17,23). CART peptides are widely distributed in the CNS and are known to suppress food intake (24,25) and stimulate Fos expression in a number of brain areas when administered centrally (26,27). Leptin-induced Egr1 expression has been shown to increase the sensitivity of vagal afferent neurons to CCK, thereby inhibiting food intake (17,27).…”

Section: Disscussionmentioning

confidence: 99%

“…CART peptides are widely distributed in the CNS and are known to suppress food intake (24,25) and stimulate Fos expression in a number of brain areas when administered centrally (26,27). Leptin-induced Egr1 expression has been shown to increase the sensitivity of vagal afferent neurons to CCK, thereby inhibiting food intake (17,27). Therefore, it was suggested that Egr1-induced CART expression and hypersensitivity to CCK was responsible, at least partially, for the anorexia phenotype in ARP neuron-ablated mice, although functional analysis of the ARP neural circuitry is required to test this hypothesis.…”

Section: Disscussionmentioning

confidence: 99%

Functional profiling of immediate early gene Egr1 in an anorexic mouse model

Huang

Jiang

Yuan

2013

Molecular Medicine Reports

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Abstract.A small population of neurons in the hypothalamus is known to promote food intake by releasing inhibitory agouti-related peptide (ARP) and neuropeptide Y to broad postsynaptic areas. Acute ablation of ARP neurons in adult mice leads to rapid loss of appetite and the development of an anorexic phenotype. Recent studies have suggested that ablation of ARP neurons removes critical inhibition of postsynaptic neurons, resulting in hyperexcitation of selected downstream neurons. Left uncontrolled, this neuronal hyperactivation is hypothesized to induce starvation. However, the cellular mechanism underlying the control of excitability of postsynaptic neurons in response to the ablation of ARP neurons is poorly understood. The present study aimed to determine the functional correlation between ARP neurons and an immediate early gene, early growth response factor-1 (Egr1), in postsynaptic neurons in the context of energy homeostasis. Egr1 expression levels were analyzed in different postsynaptic areas upon acute ablation of ARP neurons. As ARP neurons increase appetite by inhibiting the pro-opiomelanocortin pathway, it was also investigated whether blockade of melanocortin signaling affects Egr1 expression in ARP neuron-ablated mice. The results suggested that ablation of ARP neurons induced robust expression of Egr1 in numerous common postsynaptic targets of ARP and pro-opiomelanocortin neurons. When ARP neurons were acutely ablated, it was demonstrated that Egr1 induction was attenuated by chronic blockade of the melanocortin signaling pathway in the arcuate nucleus, but not in other downstream regions. Further analysis of the Egr1 signaling cascade may aid in differentiating the functional involvement of postsynaptic targets of ARP neurons in the control of energy metabolism.

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“…In vitro, leptin and CCK synergistically increase phosphorylated STAT3 production in the nodose ganglion, which contains the cell bodies of the vagal afferent neurons (20). Other studies have reported that CCK interacts with leptin at the level of the vagal afferent neurons to control the function of early growth response factor 1 (8,9). However, the molecular mechanisms of CCK and leptin interaction in the hypothalamus have not been fully elucidated.…”

mentioning

confidence: 99%

Coinjection of CCK and leptin reduces food intake via increased CART/TRH and reduced AMPK phosphorylation in the hypothalamus

Akieda-Asai

Poleni

Date

2014

American Journal of Physiology-Endocrinology and Metabolism

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Akieda-Asai S, Poleni PE, Date Y. Coinjection of CCK and leptin reduces food intake via increased CART/TRH and reduced AMPK phosphorylation in the hypothalamus. Am J Physiol Endocrinol Metab 306: E1284 -E1291, 2014. First published April 8, 2014 doi:10.1152/ajpendo.00664.2013.-CCK and leptin are anorectic hormones produced in the small intestine and white adipose tissue, respectively. Investigating how these hormones act together as an integrated anorectic signal is important for elucidating the mechanisms by which energy balance is maintained. We found here that coadministration of subthreshold CCK and leptin, which individually have no effect on feeding, dramatically reduced food intake in rats. Phosphorylation of AMP-activated protein kinase (AMPK) in the hypothalamus significantly decreased after coinjection of CCK and leptin. In addition, coadministration of these hormones significantly increased mRNA levels of anorectic cocaine-and amphetamineregulated transcript (CART) and thyrotropin-releasing hormone (TRH) in the hypothalamus. The interactive effect of CCK and leptin on food intake was abolished by intracerebroventricular preadministration of the AMPK activator AICAR or anti-CART/anti-TRH antibodies. These findings indicate that coinjection of CCK and leptin reduces food intake via reduced AMPK phosphorylation and increased CART/TRH in the hypothalamus. Furthermore, by using midbrain-transected rats, we investigated the role of the neural pathway from the hindbrain to the hypothalamus in the interaction of CCK and leptin to reduce food intake. Food intake reduction induced by coinjection of CCK and leptin was blocked in midbrain-transected rats. Therefore, the neural pathway from hindbrain to hypothalamus plays an important role in transmitting the anorectic signals provided by coinjection of CCK and leptin. Our findings give further insight into the mechanisms of feeding and energy balance. cholecystokinin; food intake; leptin; midbrain transection FOOD INTAKE IS FINELY REGULATED by a complicated interaction of many orexigenic and anorectic signals produced in the brain and peripheral tissues. To maintain energy balance, information on the metabolic state resulting from feeding-related factors must be transported efficiently to the brain. Leptin, an anorectic hormone produced by white adipose tissue, plays an important role in maintaining energy balance (47). Absence of leptin results in severe obesity in both rodents and humans (13,38). Leptin directly binds to its ObRb receptors, which are located mainly in the hypothalamus and hindbrain; it promotes energy expenditure by stimulating the Janus-activated kinase (JAK)-STAT3 signaling pathway (4). Leptin also inhibits AMP-activated protein kinase (AMPK) activity in the arcuate nucleus and paraventricular nucleus of the hypothalamus (33). Moreover, leptin administration enhances the anorectic response to satiety-signaling molecules such as bombesin (26) or amylin (52).CCK is a gastrointestinal hormone produced by I cells of the proximal small intestine ...

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Leptin Resistance in Vagal Afferent Neurons Inhibits Cholecystokinin Signaling and Satiation in Diet Induced Obese Rats

Cited by 120 publications

References 46 publications

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

Functional profiling of immediate early gene Egr1 in an anorexic mouse model

Coinjection of CCK and leptin reduces food intake via increased CART/TRH and reduced AMPK phosphorylation in the hypothalamus

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