Orexin, serotonin, and energy balance

Vijayakumar Mavanji, Brianna Pomonis, Catherine M. Kotz

Research output: Contribution to journalReview articlepeer-review

17 Scopus citations


The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis. Physical activity is comprised of intentional exercise and SPA. These are opposite ends of a continuum of physical activity intensity and structure. Non-goal-oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high-intensity voluntary exercise. In animals, SPA is activity not influenced by rewards such as food or a running wheel. Spontaneous physical activity in humans and animals burns calories and could theoretically be manipulated pharmacologically to expend calories and protect against obesity. The DRN neurons receive orexin inputs, and project heavily onto cortical and subcortical areas involved in movement, feeding and energy expenditure (EE). This review discusses the function of hypothalamic orexin in energy-homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin-serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin–serotonin cross-talk; the role of serotonin receptors, transporters and uptake-inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin-function; single-nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin–serotonin field. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.

Original languageEnglish (US)
Article numbere1536
JournalWIREs mechanisms of disease
Issue number1
StatePublished - Jan 1 2022

Bibliographical note

Funding Information:
The authors would like to thank Dr. Claudio Perez-Leighton of the Departmento de Fisiologia, facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile, for his help with the preparation of Figure 1.

Publisher Copyright:
© 2021 The Authors. WIREs Mechanisms of Disease published by Wiley Periodicals LLC.


  • energy expenditure
  • orexin
  • physical activity
  • serotonin

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Review


Dive into the research topics of 'Orexin, serotonin, and energy balance'. Together they form a unique fingerprint.

Cite this