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Orexin: Pathways to obesity resistance?

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Abstract

Obesity has increased in prevalence worldwide, attributed in part to the influences of an obesity-promoting environment and genetic factors. While obesity and overweight increasingly seem to be the norm, there remain individuals who resist obesity. We present here an overview of data supporting the idea that hypothalamic neuropeptide orexin A (OXA; hypocretin 1) may be a key component of brain mechanisms underlying obesity resistance. Prior work with models of obesity and obesity resistance in rodents has shown that increased orexin and/or orexin sensitivity is correlated with elevated spontaneous physical activity (SPA), and that orexin-induced SPA contributes to obesity resistance via increased non-exercise activity thermogenesis (NEAT). However, central hypothalamic orexin signaling mechanisms that regulate SPA remain undefined. Our ongoing studies and work of others support the hypothesis that one such mechanism may be upregulation of a hypoxia-inducible factor 1 alpha (HIF-1α)-dependent pathway, suggesting that orexin may promote obesity resistance both by increasing SPA and by influencing the metabolic state of orexin-responsive hypothalamic neurons. We discuss potential mechanisms based on both animal and in vitro pharmacological studies, in the context of elucidating potential molecular targets for obesity prevention and therapy.

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Abbreviations

DIO:

Diet-induced obese

DR:

Diet-resistant

ERK1/2:

Extracellular receptor kinase 1 and 2

FIH:

Factor inhibiting HIF

HA:

High-activity

HCR:

High caloric restriction

HEK:

Human embryonic kidney

HIF-1α:

Hypoxia-inducible factor 1 alpha

LA:

Low-activity

LCR:

Low caloric restriction

MAPK:

Mitogen-activated protein kinase

MKP-1:

MAPK-phosphatase-1

NEAT:

Non-exercise activity thermogenesis

OP:

Obesity-prone

OR:

Obesity-resistant

OX1R:

Orexin/hypocretin 1 receptor

OX2R:

Orexin/hypocretin 2 receptor

OXA:

Orexin A (Hypocretin 1)

OXB:

Orexin B (Hypocretin 2)

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha

PKA:

Protein kinase A

PKC:

Protein kinase C

PLC:

Phospholipase C

POMC:

Pro-opiomelanocortin

PTX:

Pertussis toxin

rLH:

Rostral lateral hypothalamic area

SPA:

Spontaneous physical activity

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Acknowledgments

Authors received support from the US Department of Veterans Affairs Rehabilitation Research and Development, Veterans Affairs grant BX001686, and R01 DK078985.

Conflict of interest

The authors declared that they have no any potential conflict of interest relevant to this article.

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Authors and Affiliations

  1. Department of Veterans Affairs, Minneapolis Veterans Affairs Health Care System, 151-Research Service, Geriatric Research Education and Clinical Center (GRECC), One Veterans Drive, Minneapolis, MN, 55417, USA

    Tammy A. Butterick, Catherine M. Kotz & Joshua P. Nixon

  2. Department of Food Science and Nutrition, 225 Food Science and Nutrition, 1334 Eckles Ave, St. Paul, MN, 55108, USA

    Tammy A. Butterick, Charles J. Billington, Catherine M. Kotz & Joshua P. Nixon

  3. Department of Medicine, Minneapolis Veterans Affairs Health Care System, 151-Research Service, Geriatric Research Education and Clinical Center (GRECC), One Veterans Drive, Minneapolis, MN, 55417, USA

    Charles J. Billington

  4. Department of Medicine, University of Minnesota Medical School, Suite 14-110 Phillips-Wangensteen Bldg 420 Delaware Street SE, MMC 194, Minneapolis, MN, 55455, USA

    Charles J. Billington

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  1. Tammy A. Butterick
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Correspondence to Tammy A. Butterick.

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Butterick, T.A., Billington, C.J., Kotz, C.M. et al. Orexin: Pathways to obesity resistance?. Rev Endocr Metab Disord 14, 357–364 (2013). https://doi.org/10.1007/s11154-013-9259-3

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