High fat diet induces specific pathological changes in hypothalamic orexin neurons in mice

Nobunaga, Mizuki; Obukuro, Kanae; Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Tsutsui, Masato; Katsuki, Hiroshi

doi:10.1016/j.neuint.2014.09.002

Cited by 32 publications

(21 citation statements)

References 19 publications

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“…We also noted that HFD trended to increase orexin neurons in the lateral hypothalamus, independent of time spent on HFD. This result does not support previously published work (45) but again this previous published study did not employ robust stereological methods to quantify orexin neurons. We also observed a significant reduction in orexin cell volume in the lateral hypothalamus.…”

Section: Discussioncontrasting

confidence: 99%

A Stereological Analysis of NPY, POMC, Orexin, GFAP Astrocyte, and Iba1 Microglia Cell Number and Volume in Diet-Induced Obese Male Mice

et al. 2015

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The hypothalamic arcuate nucleus (ARC) contains 2 key neural populations, neuropeptide Y (NPY) and proopiomelanocortin (POMC), and, together with orexin neurons in the lateral hypothalamus, plays an integral role in energy homeostasis. However, no studies have examined total neuronal number and volume after high-fat diet (HFD) exposure using sophisticated stereology. We used design-based stereology to estimate NPY and POMC neuronal number and volume, as well as glial fibrillary acidic protein (astrocyte marker) and ionized calcium-binding adapter molecule 1 (microglia marker) cell number in the ARC; as well as orexin neurons in the lateral hypothalamus. Stereological analysis indicated approximately 8000 NPY and approximately 9000 POMC neurons in the ARC, and approximately 7500 orexin neurons in the lateral hypothalamus. HFD exposure did not affect total neuronal number in any population. However, HFD significantly increased average NPY cell volume and affected NPY and POMC cell volume distribution. HFD reduced orexin cell volume but had a bimodal effect on volume distribution with increased cells at relatively small volumes and decreased cells with relatively large volumes. ARC glial fibrillary acidic protein cells increased after 2 months on a HFD, although no significant difference after 6 months on chow diet or HFD was observed. No differences in ARC ionized calcium-binding adapter molecule 1 cell number were observed in any group. Thus, HFD affects ARC NPY or POMC neuronal cell volume number not cell number. Our results demonstrate the importance of stereology to perform robust unbiased analysis of cell number and volume. These data should be an empirical baseline reference to which future studies are compared.

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Section: Discussioncontrasting

confidence: 99%

A Stereological Analysis of NPY, POMC, Orexin, GFAP Astrocyte, and Iba1 Microglia Cell Number and Volume in Diet-Induced Obese Male Mice

et al. 2015

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“…Here, we show that long-term OX-A overactivity due to lack of leptin signaling contributes to obesity instead via endocannabinoid-mediated suppression of POMC expression and hyperphagia, because the selective OX-1R antagonist SB334867 reduced body weight and food intake at doses ineffective on sleep duration and locomotion. Similarly to what was found in the periaqueductal gray (7) or in other LH target areas (20), also in the ARC of ob/ob and HFD-fed mice we found the increase of OX-A trafficking and release to terminals as well as the compensatory reduction or no change in the levels of prepro-OX and OX-A in the LH (20,39). The present discovery of an orexin/endocannabinoid/melanocortin interaction, and its impact on hyperphagia, obesity, and fatty liver, calls for investigations on potential synergies between OX-1R antagonists and/or CB 1 R antagonists and/or MC4R agonists, aiming at counteracting eating disorders such as binge eating, but also obesity and .…”

Section: Discussionsupporting

confidence: 87%

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

Morello

Imperatore

Palomba

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocytestimulating hormone (α-MSH) promote satiety. POMC neurons receive orexin-A (OX-A)-expressing inputs and express both OX-A receptor type 1 (OX-1R) and cannabinoid receptor type 1 (CB 1 R) on the plasma membrane. OX-A is crucial for the control of wakefulness and energy homeostasis and promotes, in OX-1R-expressing cells, the biosynthesis of the endogenous counterpart of marijuana's psychotropic and appetite-inducing component Δ 9 -tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB 1 R. We report that OX-A/OX-1R signaling at POMC neurons promotes 2-AG biosynthesis, hyperphagia, and weight gain by blunting α-MSH production via CB 1 R-induced and extracellularsignal-regulated kinase 1/2 activation-and STAT3 inhibitionmediated suppression of Pomc gene transcription. Because the systemic pharmacological blockade of OX-1R by SB334867 caused anorectic effects by reducing food intake and body weight, our results unravel a previously unsuspected role for OX-A in endocannabinoid-mediated promotion of appetite by combining OX-induced alertness with food seeking. Notably, increased OX-A trafficking was found in the fibers projecting to the ARC of obese mice (ob/ob and high-fat diet fed) concurrently with elevation of OX-A release in the cerebrospinal fluid and blood of mice. Furthermore, a negative correlation between OX-A and α-MSH serum levels was found in obese mice as well as in human obese subjects (body mass index > 40), in combination with elevation of alanine aminotransferase and γ-glutamyl transferase, two markers of fatty liver disease. These alterations were counteracted by antagonism of OX-1R, thus providing the basis for a therapeutic treatment of these diseases.hypocretin-1 | cannabinoid type 1 receptor | 2-arachidonoylglycerol | α-melanocyte-stimulating hormone | hypothalamus E merging anatomical, biochemical, and pharmacological evidence supports a functional interaction between endocannabinoids and orexin-A (OX-A) (also known as hypocretin-1) in the hypothalamic regulation of appetite, energy expenditure, and metabolism (1). In hypothalamic neurons, the endocannabinoid 2-arachidonylglycerol (2-AG) is under the negative control of leptin (2) and acts through the cannabinoid receptor type 1 (CB 1 R) to promote appetite by activating several intracellular pathways, including mitogen-activated protein kinases of the extracellularsignal-regulated kinase (ERK) family (3). OX-A is an orexigenic neuropeptide expressed by neurons of the lateral hypothalamus (LH), which acts through the OX-A receptor type 1 (OX-1R) (4). Activation of OX-1R by OX-A signaling has been found to affect CB 1 R function by stimulating 2-AG biosynthesis via the phospholipase C/diacylglycerol lipase α (PLC/DAGL) pathway (5) and by enhancing ERK1/2 phosphorylation and activity in cells expressing both OX-1R and CB 1 R (6, 7). Proopiomelanocortin (POMC)-containing neurons represent t...

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“…Nobunaga et al demonstrated that microglial derived iNOS contributed to a loss of orexin producing neurons and subsequent metabolic dysfunction in mice fed a high fat diet [31]. Reduction of iNOS expression due to OXA modulation in our study could therefore help in maintaining a favorable environment for surrounding cells.…”

Section: Discussionmentioning

confidence: 59%

Role of orexin A signaling in dietary palmitic acid-activated microglial cells

Duffy

Yuan

Wisdorf

et al. 2015

Neuroscience Letters

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Excess dietary saturated fatty acids such as palmitic acid (PA) induce peripheral and hypothalamic inflammation. Hypothalamic inflammation, mediated in part by microglial activation, contributes to metabolic dysregulation. In rodents, high fat diet-induced microglial activation results in nuclear translocation of nuclear factor-kappa B (NFκB), and increased central pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). The hypothalamic neuropeptide orexin A (OXA, hypocretin 1) is neuroprotective in brain. In cortex, OXA can also reduce inflammation and neurodegeneration through a microglial-mediated pathway. Whether hypothalamic orexin neuroprotection mechanisms depend upon microglia is unknown. To address this issue, we evaluated effects of OXA and PA on inflammatory response in immortalized murine microglial and hypothalamic neuronal cell lines. We demonstrate for the first time in microglial cells that exposure to PA increases gene expression of orexin-1 receptor but not orexin-2 receptor. Pro-inflammatory markers IL-6, TNF-α, and inducible nitric oxide synthase in microglial cells are increased following PA exposure, but are reduced by pretreatment with OXA. The anti-inflammatory marker arginase-1 is increased by OXA. Finally, we show hypothalamic neurons exposed to conditioned media from PA-challenged microglia have increased cell survival only when microglia were pretreated with OXA. These data support the concept that OXA may act as an immunomodulatory regulator of microglia, reducing pro-inflammatory cytokines and increasing anti-inflammatory factors to promote a favorable neuronal microenvironment.

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High fat diet induces specific pathological changes in hypothalamic orexin neurons in mice

Cited by 32 publications

References 19 publications

A Stereological Analysis of NPY, POMC, Orexin, GFAP Astrocyte, and Iba1 Microglia Cell Number and Volume in Diet-Induced Obese Male Mice

A Stereological Analysis of NPY, POMC, Orexin, GFAP Astrocyte, and Iba1 Microglia Cell Number and Volume in Diet-Induced Obese Male Mice

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

Role of orexin A signaling in dietary palmitic acid-activated microglial cells

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