Nucleus tractus solitarii (NTS) and appetite

Introduction
Here I am building up a story about the importance of NTS in the regulation of appetite. I start off with introducing leptin and then talk about its signalling pathway and how the response to leptin can be measured. After that I mention why we should look at the NTS in relation to appetite regulation and finally give some evidence of the effect leptin plays in appetite regulation in the NTS.

Leptin
- is synthesised predominantly in adipose tissue (Zhang et al, 1994) in proportion to fat mass, but also in skeletal muscle (Wang et al, 1998) and stomach (Bado et al, 1998)
- acts (in terms of the regulation of appetite) on arcuate nucleus (ARC) to stimulate anorexic POMC/CART neurones and to inhibit AgRP/NPY neurones, which results in a reduced food intake (anorexic effect of leptin) and increased energy expenditure
- acts via leptin receptors (LepR); there are 6 isoforms LepRa-f which are made from one gene by alternative splicing; the majority of leptin's effect is assigned to LepRb (i.e. the long form of the receptor)
- leptin mediates its effect on a cell via a JAK-STAT pathway

JAK-STAT pathway
- there are seven mammalian STAT family members (STAT1-STAT4, STAT5A and B, STAT6)
- STAT = signal transducers and activators of transcription
- leptin has been associated with STAT3, which has three isoforms (alpha, beta, gamma)
- JAK = Jason kinase (of tyrosine residues)
- upon leptin binding to LepRb, JAK phosphorylates tyrosine residues of the intracellular part of the receptor which attracts STAT3, which is phosphorylated itself by JAK
- phosphorylated STAT3 (pSTAT3) forms dimers and migrates to cell nuclei to activate gene transcription: (Image from Pedranzini et al., 2004)

- in this way, leptin results in synthesis of proteins which then mediate the effect of leptin on e.g. appetite and energy expenditure
- in a lab, pSTAT3 is used as an indicator of cellular (e.g. neuronal) activity in response to leptin; an example of a technique is immunohistochemistry & microscopy using antibodies developed against pSTAT3

Why look at NTS?
- as mentioned in the previous post, NTS is receives and processes signals from the mouth and the gastrointestinal tract, sensing taste and nutrients
- its neuroness project to other areas of the brain which are involved in the regulation of appetite, e.g. hypothalamic nuclei and other parts of brainstem
- so NTS is in a good position to be involved in the appetite regulation

NTS, leptin and appetite
- NTS neurones have increased pSTAT3 levels after peripheral leptin administration (Ellacott et al, 2006), which leads us to believe that they express LepRs
- indeed, NTS neurones express LepR as was shown by studies of mouse models with fluorescent proteins under the control of LepR promoters
- this means that neurones which have active promoter of the LepR gene, and thus most likely express the LepR, will also express the fluorescent protein, which is under the control of the same promoter as the LepR
- leptin administration to the NTS produces hypophagia and weight loss
- rats with LepR knocked-down by AAV-shRNAi in NTS and area postrema (AP) have chronic hyperphagia (Hayes et al, 2010)

Nucleus tractus solitarii (NTS) - Introduction

Introduction
I am starting with a general introduction composed of unreferenced materials (warning!) and images and with no reference to appetite.

Name
- nucleus tractus solitarii in latin
- nucleus of the solitary tract in English
- NTS

Location
- located in the brainstem along the length of the medulla with a small portion in the lower pons
Brainstem, dorsal view:

- is a part of the dorsal vagal complex (DVC), together with area postrema and dorsal motor nucleus of the vagus
- is divided into rostral and caudal regions
- has probably a very similar location in human, mouse and rat brains
Human brain, frontal plane (top left), horizontal plane (bottom left), median plane (right):

Human brain, median plane:

Mouse brain, horizontal plane:


Anatomy
- axons (white matter) run in the middle of the nucleus
- nucleus (grey matter) surround the axons
- interesting: this stands out on a stained section, which is where the name solitary comes from
- sub regions of the NTS can be related to the distribution of inputs:
- contacts from cranial primary afferent neurons related to cardiovascular, respiratory and gastrointestinal functions
- a degree of localization within the caudal region:
- many cardiovascular neurons sit near the midline of the nucleus
- many respiratory related neurons are located laterally within the nucleus

Inputs
- afferent taste information from nerves VII, IX and X
Taste receptor cell and its link to NTS:
Figure caption here:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=frrec&part=ch10&rendertype=figure&id=ch10.f1

- affarens from chemoreceptors in the carotid (via IX) and aortic bodies (via X)
- affarens from arterial baroreceptors from the aorta and carotid arteries called arterial baroreceptors
- chemically and mechanically sensitive neurons with endings in the heart, lungs & airways, gastrointestinal system, liver and other viscera (mostly via cranial nerves IX and X that directly enter the brainstem to form synapses within the caudal two-thirds of the NTS)

Function
- neurons mediate the gag reflex, the carotid sinus reflex, the aortic reflex, the cough reflex, the baroreceptor and chemoreceptor reflexes, several respiratory reflexes and reflexes within the gastrointestinal system regulating motility and secretion
Reflex arcs:

- also receives information about the gut wall, as well as stretch of the lungs and dryness of mucous membranes
- these first central neurons (here within the NTS) can participate in autonomic reflexes that may be as simple as two central neurons with the second neuron being an efferent or motor neuron that projects back directly to the organ such as the heart forming some of the simplest reflex pathways in the brain

* * *
Sources
Text: Wikipedia
Images: from Google Images

Where to start

What is it all about: This blog is created as a dynamic system of notes on the regulation of appetite by one student of this exciting area.

The purpose is to: take notes, organise my thoughts, practise expressing myself and scientific writing. This means quite entirely for my benefit. But it would be great if others could find this information useful one day.

How this is going to happen: My idea is a dynamic content which is being corrected and filled in as I find out more. If an expert finds his or her way, or anybody else for that matter, who wants to read any of this and contribute, you are welcome to do so!

Disclaimer: Please keep in your mind, that a student does not mean an expert, that these are notes not textbooks and that this material is not peer- or anybody else-reviewed, i.e. may not be correct but instead may be full of mistakes.