Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation

Naznin, Farhana; Koji, Takehiko; Waise, T.M. Zaved; Namkoong, Churl; Moin, Abu Saleh Md; Sakoda, Hideyuki; Nakazato, Masamitsu

doi:10.1530/joe-15-0139

Cited by 86 publications

(91 citation statements)

References 45 publications

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“…In a recent study, we showed that 12-week HFD feeding (60% of calories as fat) induced accumulation and activation of M1 (Iba1 + /CD86 + ) macrophages both in the nodose ganglion and hypothalamus of mice [18]. In the one-day HFD study described here we observed elevated recruitment of M1 macrophages in the nodose ganglion but not in the hypothalamus, suggesting that the nodose ganglion receives inflammatory signals before the hypothalamus.…”

Section: Discussionsupporting

confidence: 50%

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice

Waise

Koji

Naznin

et al. 2015

Biochemical and Biophysical Research Communications

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121

102

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A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation.

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Section: Discussionsupporting

confidence: 50%

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice

Waise

Koji

Naznin

et al. 2015

Biochemical and Biophysical Research Communications

Self Cite

121

102

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“…DIO also attenuates fasting-induced hyperphagia by suppressing arcuate neuronal activation and hypothalamic NPY/AgRP mRNA expression [16], showing that DIO affects other physiological cues designed to maintain energy homeostasis. The effects of DIO on ghrelin resistance are not limited to food intake, as ghrelin fails to reduce oxygen consumption in HFD-fed mice relative to chow-fed mice [58]. …”

Section: Positive Energy Balance and Ghrelin Resistancementioning

confidence: 99%

Obesity Impairs the Action of the Neuroendocrine Ghrelin System

Zigman

Bouret

Andrews

2016

Trends in Endocrinology & Metabolism

118

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Ghrelin is a metabolic hormone that promotes energy conservation by regulating appetite and energy expenditure. Although some studies suggest that antagonizing ghrelin function attenuates body weight gain and glucose intolerance on a high calorie diet, there is little information about the metabolic actions of ghrelin in the obese state. In this review, we discuss the novel concept of obesity-induced central ghrelin resistance in neural circuits regulating behavior, and impaired ghrelin secretion from the stomach. Interestingly, weight loss restores ghrelin secretion and function, and we hypothesize that ghrelin resistance is a mechanism designed to protect a higher body weight set-point established during times of food availability, to maximize energy reserves during a time of food scarcity.

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“…These deficits occur after several weeks of HFD feeding (Briggs et al, 2014), and persist while body weight remains high, but can be reversed with dietinduced weight loss (Briggs et al, 2013). Others have recently demonstrated ghrelin resistance in the vagal afferents and nodose ganglion, suggesting that this phenomenon is not limited to the hypothalamus (Naznin et al, 2015). The interaction between HFD feeding and reward processing is as yet not well understood, however ghrelin resistance appears to extend to behavioural measures beyond feeding.…”

Section: Introductionmentioning

confidence: 99%

Diet-induced obesity causes ghrelin resistance in reward processing tasks

Lockie

Dinan

Lawrence

et al. 2015

Psychoneuroendocrinology

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Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1mg/kg in 10ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33μg/μl in 0.5μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice; however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing.

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Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation

Cited by 86 publications

References 45 publications

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice

Obesity Impairs the Action of the Neuroendocrine Ghrelin System

Diet-induced obesity causes ghrelin resistance in reward processing tasks

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