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Role of Orexin-A in Hypertension and Obesity

  • Hypertension and Metabolic Syndrome (J Sperati, Section Editor)
  • Published:
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Abstract

Purpose of Review

Hypertension is one of the most challenging health problems inducing cerebrovascular disease and high percentage of death when associated with diabetes, dyslipidemias, and obesity. Orexin/hypocretin is a peptide expressed by a small number of neurons of the dorsolateral hypothalamus, a brain feeding and autonomic “fight-or-flight” regulatory center. According to this function, orexin has been demonstrated to evoke cardiovascular responses, heart rate, hypertension, hyperarousal, hyperphagia, and obesity. The focus of this review is to provide an overview about the mechanism through which orexin regulates food intake and cardiovascular responses and its role in the pathogenesis of obesity and hypertension which could be of great interest to establish possible new therapies.

Recent Findings

In normal rats and mice, central administration of orexin increases food intake, blood pressure, and sympathetic nerve activity and these effects are blocked by selective orexin receptor antagonist SB-334867 or almorexant. Moreover, upregulation of orexin signaling, in combination with elevation of epinephrine and norepinephrine circulating levels, occurs in rats exposed to chronic stress, in models of spontaneous hypertension (SHR and BPH/2J Schlager mice) and in obese mice (ob/ob or mice fed with high fat diet). Therefore, hyperactivity of orexinergic neurons could be a factor in the development of obesity and essential hypertension.

Summary

Because of their widespread projections to the brain regions involved in appetite and cardiovascular responses, as far down as sympathetic preganglionic neurons in the spinal cord, orexin evokes sympathetically mediated cardiovascular responses. Lasting upregulation of orexin signaling can lead to hyperphagia, obesity, and hypertensive state. Dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists (SORAs) have antihypertensive effects that could be of clinical use for regulation of food intake and hypertension, supporting the role of orexinergic neurons as critical checkpoint in the neurogenic control of metabolic and cardiovascular functions.

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Abbreviations

2-AG:

2-arachidonoylglycerol

ACE:

Angiotensin-converting enzyme

ACTH:

Adreno corticotropic hormone

Amb:

Nucleus ambiguous

Ang-II:

Angiotensin II

ARC:

Arcuate nucleus

AT1:

Angiotensin type 1 receptor

AVP:

Arginine-vasopressin

BPH/2 J:

High blood pressure mouse

BPN/3 J:

Normotensive blood pressure mouse

CRF:

Corticotropin-releasing factor

CRH:

Adrenocorticotropin-releasing hormone

DMN:

Dorsomedial nucleus

Epi:

Epinephrine

GFP:

Green fluorescent protein

Hcrt1:

Hypocretin 1

Hcrt2:

Hypocretin 2

HFD:

High-fat diet

HPA:

Hypothalamic-pituitary-adrenal axis

HR:

Heart rate

i.c.v.:

Intracerebroventricular

IML:

Intermediolateral column

i.p.:

Intraperitoneal

i.v.:

Intravenous

LC:

Locus coeruleus

LHA:

Lateral hypothalamic area

LZRs:

Lean Zucker rats

MAP:

Mean arterial pressure

MSH:

Melanocyte Stimulating Hormone

NE:

Norepinephrine

NPY:

Neuropeptide-Y

NTS:

Nucleus tractus solitaries

Ox1R:

Orexin-1 receptor

Ox2R:

Orexin-2 receptor

OXRs:

Ox1R and Ox2R

OX-A:

Orexin-A

OX-B:

Orexin-B

OXs:

OX-A and OX-B

OZRs:

Obese Zucker rats

PAG:

Periaqueductal gray

POMC:

Proopiomelanocortin

PVN:

Paraventricular nucleus

RAS:

Renin-angiotensin system

RSNA:

Response sympathetic nervous autonomous

RVLM:

Rostral ventrolateral medulla

RVMM:

Rostral ventromedial medulla

s.c.:

Subcutaneous

SCN:

Supra-chiasmatic nucleus

SFD:

Standard-fat diet

SHR:

Spontaneously hypertensive rat

SIHR:

Stress-induced hypertensive rats

SNA:

Sympathetic nerve activity

SPNs:

Sympathetic preganglionic neurons

VMN:

Paraventricular nucleus

ZF:

Zona fasciculate

ZR:

Zona reticularis

WKY:

Wistar Kyoto rats

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Authors and Affiliations

  1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Viale Campi Flegrei, 80078, Pozzuoli, Italy

    Roberta Imperatore & Luigia Cristino

  2. Department of Science and Technology, University of Sannio, Benevento, Italy

    Roberta Imperatore

  3. Department of Biomolecular Science, University of Urbino “Carlo Bo”, Urbino, Italy

    Letizia Palomba

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  1. Roberta Imperatore
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Imperatore, R., Palomba, L. & Cristino, L. Role of Orexin-A in Hypertension and Obesity. Curr Hypertens Rep 19, 34 (2017). https://doi.org/10.1007/s11906-017-0729-y

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