Available online at www.sciencedirect.com Neuroscience Letters 428 (2007) 7–10 Innervation of submucosal adipocytes in the human colon Menachem Hanani a,∗ , Aviram Nissan b , Herbert R. Freund b a Laboratory of Experimental Surgery, Hebrew University-Hadassah Medical School, Mount Scopus, Jerusalem 91240, Israel b Department of Surgery, Hebrew University-Hadassah Medical School, Mount Scopus, Jerusalem 91240, Israel Received 21 July 2007; received in revised form 16 September 2007; accepted 18 September 2007 Abstract The submucosal plexus regulates various activities of the gastrointestinal mucosa. As the submucosa in the human colon contains adipose tissue we hypothesized that submucosal neurons might also innervate this tissue. We stained submucosal nerves for the enzyme NADPH-diaphorase, which is a marker for nitric oxide synthase-containing nerves. This resulted in the staining of neurons in submucosal ganglia and numerous nerve fibers throughout the submucosa. These fibers were found to be in close contact with adipocytes, and in many cases fine nerve fibers displaying varicosities were found on the surface of these cells. At least some of these fibers originated from submucosal neurons. In addition, cell bodies of submucosal neurons were in close proximity to adipocytes. It is concluded that submucosal nerves innervate adipose tissue in the submucosa, which is a novel role for these nerves, and might have important functional implications. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Submucosal plexus; NADPH diaphorase; Colon; Enteric nervous system; Adipose tissue The enteric nervous system (ENS) is the major element in the regulation of all the functions of the digestive system [12,18]. The two main divisions of the ENS are the myenteric plexus, which is located between the longitudinal and circular muscle layers and controls the mechanical activity of gastrointestinal (GI) muscles and the submucosal plexus, which is located within the submucosa, and is thought to innervate the mucosa and sub- mucosal blood vessels [12,18,20,21]. Thus submucosal nerves can influence mucosal transport and also regulate the diameter of submucosal blood vessels, thereby controlling blood flow to the mucosa. The human intestine contains fat cells, or adipocytes [14], but little is known about their function and particularly about their innervation. It has been long known that adipose tissue in other sites is innervated by postganglionic sympathetic nerves that release noradrenaline, which in turn acts on  3 receptors on fat cells, thereby inducing lipolysis. However, in recent years it was reported that brown [5] and white [11] adipose tissues are innervated also by parasympathetic nerves, which presumably release acetylcholine. These interesting findings suggested that, ∗ Corresponding author at: Laboratory of Experimental Surgery, Hadassah University Hospital, Mount Scopus, Jerusalem 91240, Israel. Tel.: +972 2 5844721; fax: +972 2 5823515. E-mail address: hananim@cc.huji.ac.il (M. Hanani). as in most tissues innervated by the autonomic nervous system, there is a dual control by this system in adipose tissue as well. It may be suggested that parasympathetic activity opposes the sympathetic one, contributing to increased storage of lipids in adipose tissue. Obviously, the clinical implications of this possi- ble mechanism to the understanding and treatment of obesity are considerable. Recently, the suggestion that white adipose tissue is innervated by parasympathetic nerves was met with criticism [3,6], and it appears that further work needs to be done to clarify this issue. The observation that white adipose tissue is not innervated exclusively by sympathetic nerves raised the possibility that this tissue receives non-cholinergic, non-adrenergic innervation, as found in other systems, such as the GI and urinary tracts. One of the most abundant neurotransmitters in peripheral organs is nitric oxide (NO), which has been found to have many important physiological roles [24]. There are reports that NO has physio- logical effects on adipose tissue [15], but there is no information on a possible innervation of this tissue by nitrergic fibers. The aim of this work was to answer the question of whether submu- cosal nerves, and specifically those that synthesize NO, innervate submucosal adipocytes. Tissues were obtained from 14 patients (5 females, 9 males), undergoing elective surgery for colonic cancer. Patients’ median age was 61 years (range 25–85 years). The use of the tissues was approved by the Institutional Helsinki Committee. Full thickness 0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2007.09.038