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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\u2010goal\u2010oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high\u2010intensity 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\u2010homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin\u2010serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin\u2013serotonin cross\u2010talk; the role of serotonin receptors, transporters and uptake\u2010inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin\u2010function; single\u2010nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin\u2013serotonin field.<\/jats:p>\n                  <jats:p>\n                    This article is categorized under:\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:p>Metabolic Diseases &gt; Molecular and Cellular Physiology<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  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