Decreased serotonin transporter immunoreactivity in the human hypothalamic infundibular nucleus of overweight subjects

Abstract

Context: That serotonin plays a role in the regulation of feeding behavior and energy metabolism has been known for a long time. Serotonin transporters (SERT) play a crucial role in serotonin signaling by regulating its availability in the synaptic cleft. The neuroanatomy underlying serotonergic signaling in humans is largely unknown, and until now, SERT immunoreactivity in relation to body weight has not been investigated.

Objective: To clarify the distribution of SERT immunoreactivity throughout the human hypothalamus and to compare SERT immunoreactivity in the infundibular nucleus (IFN), the human equivalent of the arcuate nucleus, in lean and overweight subjects.

Design: First, we investigated the distribution of serotonin transporters (SERT) over the rostro-caudal axis of six post-mortem hypothalami by means of immunohistochemistry. Second, we estimated SERT immunoreactivity in the IFN of lean and overweight subjects. Lastly, double-labeling of SERT with Neuropeptide Y (NPY) and melanocortin cell populations was performed to further identify cells showing basket-like SERT staining.

Results: SERT-immunoreactivity was ubiquitously expressed in fibers throughout the hypothalamus and was the strongest in the IFN. Immunoreactivity in the IFN was lower in overweight subjects (p = 0.036). Basket-like staining in the IFN was highly suggestive of synaptic innervation. A very small minority of cells showed SERT double labeling with NPY, agouti-related protein and α-melanocyte stimulating hormone.

Conclusions: SERT is ubiquitously expressed in the human hypothalamus. Strong SERT immunoreactivity, was observed in the IFN a region important for appetite regulation, in combination with lower SERT immunoreactivity in the IFN of overweight and obese subjects, may point toward a role for hypothalamic SERT in human obesity.

Keywords: SERT; arcuate nucleus; hypothalamus; obesity; paraventricular nucleus.

Figure 1

(A) Schematic illustration of the distribution of immunoreactive serotonin transporter (SERT) fibers in coronal sections (rostral and caudal) of the human hypothalamus. Abbreviations: AC, anterior commissure; BST, bed nucleus of the striae terminalis; DBB, diagonal band of Broca; FO, fornix; IFN, infundibular nucleus; LV, lateral ventricle; NTL, lateral tuberal nucleus; OT, optic tract; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; SDN, sexually dimorphic nucleus; SON, supraoptic nucleus; TMN, tuberomamillary nucleus; III, third ventricle. (B) SERT staining, ependymal layer at the level of the PVN bar = 100 μm, (C) suprachiasmatic nucleus, bar = 250 μm, (D) infundibular nucleus, bar = 500 μm. ^*Indicates the third ventricle. High power inserts are from the same anatomical structures.

Figure 2

(A) SERT immunoreactivity in lean vs. overweight subjects. Illustration of SERT staining in the infundibular nucleus of a lean (B) and an obese (C) subject.

Figure 3

A series of immunofluorescent photomicrographs showing serotonin transporter (SERT)- immunostaining (shown in green) combined with markers for major cell types (shown in red) of suprachiasmatic nucleus (SCN) and infundibular nucleus (IFN). Cell nuclei are shown in blue. SERT immunofluorescent staining (green) combined with (A) arginine vasopressin (AVP, red) in the SCN, high power insert shows SERT staining in close proximity of AVP-positive neurons which was observed in a very small minority of cells; (B) Vasointestinal peptide (VIP, red), high power insert illustrates the absence of SERT immunoreactivity surrounding VIP-positive neurons; (C) Neuropeptide Y (NPY, red), and (D) αMelanocyte stimulating hormone (αMSH, red), note the SERT staining surrounding the αMSH positive neurons.

Figure 4

Immunofluorescent photomicrographs showing serotonin transporter (SERT)-immunostaining (shown in green) combined with immunostaining for Agouti Related Peptide (AGRP) (shown in red). Cell nuclei are shown in blue. (A) The IFN of subject 00007. Note heavily stained SERT-positive fibers. The high power insert shows basket-like SERT staining surrounding neurons which are not immunoreactive for AGRP (B) The IFN of subject 01005. The high power insert shows an AGRP immunoreactive cell surrounded by SERT-positive fiber, suggesting nerve ending.