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Reviews in Endocrine and Metabolic Disorders

, Volume 14, Issue 4, pp 357–364 | Cite as

Orexin: Pathways to obesity resistance?

  • Tammy A. Butterick
  • Charles J. Billington
  • Catherine M. Kotz
  • Joshua P. Nixon
Article

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.

Keywords

Orexin (hypocretin) Hypothalamus Obesity Spontaneous physical activity 

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

Notes

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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Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Tammy A. Butterick
    • 1
    • 2
  • Charles J. Billington
    • 2
    • 3
    • 4
  • Catherine M. Kotz
    • 1
    • 2
  • Joshua P. Nixon
    • 1
    • 2
  1. 1.Department of Veterans AffairsMinneapolis Veterans Affairs Health Care SystemMinneapolisUSA
  2. 2.Department of Food Science and NutritionSt. PaulUSA
  3. 3.Department of MedicineMinneapolis Veterans Affairs Health Care SystemMinneapolisUSA
  4. 4.Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisUSA

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