The role of hypothalamic peptides in the regulation of appetite

  • Leng, Gareth (Principal Investigator)
  • Ludwig, Mike (Co-investigator)

Project Details

Description

A major purpose of fundamental research into appetite is to identify targets for the development of new therapies to treat obesity. To validate a potential target, it is necessary to show that that target has a specific and important role in appetite regulation, and that it is potentially amenable to selective interventions. The VMH has a key role in appetite regulation, and thus provides a potential source of targets for selective intervention. However, we need to understand exactly how subpopulations of VMH neurons in vivo interact with other important regulatory systems. In this project, we will establish the interaction of VMH neurons with -MSH and oxytocin. -MSH and oxytocin are potent appetite inhibitors, and receptors for both are expressed in the VMH; we believe that it is likely that oxytocin mediates some of the actions of -MSH, and intend to test this hypothesis.
Our most general objective is to understand better how peptides released in the brain can generate coherent changes in behaviour. More specifically, we aim to understand better the mechanisms of appetite regulation in the brain. Precisely, we will test the hypothesis that regulation of satiety is modulated by the VMH, which is the final target for the interaction between -MSH and oxytocin. This project will involve experiments on anaesthetised rats in vivo to a) record the electrical activity of VMH neurons and characterise the properties of the different VMH neuronal populations, b) stimulate the release of oxytocin in the hypothalamus and record its effects on the activity of VMH neurons, c) stimulate -MSH release in the hypothalamus and measure its consequences on oxytocin release. In Part 1, we will characterise VMH neurons by their electrical properties and their responses to electrical and pharmacological stimuli, and test their responses to α-MSH and oxytocin. In Part 2, we will test whether α-MSH acts directly on the VMH, or indirectly via the release of oxytocin, or both.

Layman's description

In the UK (and worldwide), the rapidly rising prevalence of obesity is putting a massive strain on NHS resources, and there is an acute need for new drugs that restrict appetite. Our understanding of how appetite is regulated has advanced only relatively recently, since the discovery of leptin in 1994 and ghrelin in 2000, and is still at a relatively undeveloped stage. We know that one particular part of the hypothalamus - the ventromedial nucleus - seems to play an important role in satiety, but exactly what signals it responds to is not clear. Here we sought to study whether the VMH mediates the effects of two peptides - oxytocin and MSH - that are known to affect appetite, to see if these actions might be suitable targets for the development of anti-obesity drugs.

Key findings

Work on this project led to some novel and unexpected findings. The first, completely unexpected finding was that while the VMH is strongly affected by appetite related stimuli, it clearly does not mediate the satiety-inducing effects of CCK (the major peripheral appetite-inhibiting factor) by neuronal excitation. This was a key part of our hypothesis, as CCK is not only a potent mediator of satiety but is also a potent stimulator of oxytocin release, which is also itself a potent satiety factor. This raised a number of novel questions – what exactly is the role of the VMN in regulation of energy balance – and we are now pursuing the hypothesis that its major role is not in mediating satiety per se but on orchestrating the counter-regulatory glucagon response to food intake, which would be consistent with the opposite effects of insulin and leptin on VMH neurons (insulin actions in the VMN potentiate glucagon release), and consistent also with the stimulatory effect of oxytocin on glucagon release (Fujiwara Y et al.(2007) Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice. J Endocrinol. 2007 192:361-9). An important lead in understanding this was an incidental, surprising finding that i.v. secretin is an extremely potent stimulator of oxytocin neurones ( ) – much more potent than CCK, but secretin has relatively modest effects if any on food intake according to published studies and confirmed by ourselves (in a simple fasting/re-feeding model); however, importantly, although secretin stimulates the electrical activity of oxytocin cells it does not stimulate dendritic oxytocin release.



Another unexpected finding was the direct stimulatory effect of leptin on SON oxytocin (and vasopressin) neurons. This is consistent with the recently reported stimulation of oxytocin expression by leptin (Tung et al 2009), and is consistent with increasing evidence from a variety of sources of a key role for oxytocin in appetite regulation.



Publications supported by this grant to date, in whole or in part:

Sabatier N, Leng G (2008) Spontaneous discharge characteristic of neurons in the ventromedial nucleus of the rat hypothalamus in vivo. Eur J Neurosci. 2008 28:693-706.

Sabatier N, Leng G (2010) Responses to cholecystokinin in the ventromedial nucleus of the rat hypothalamus in vivo. European Journal of Neuroscience ;31:1127-35.

Takayanagi Y, Matsumoto H, Nakata M, Mera T, Fukusumi S, Hinuma S, Ueta Y, Yada T, Leng G, Onaka T. Endogenous prolactin-releasing peptide regulates food intake in rodents J Clin Invest. 2008 Dec;118(12):4014-24. doi: 10.1172/JCI34682. Epub 2008 Nov 3. Erratum in: J Clin Invest. 2009 Feb;119(2):422.

Velmurugan S, Brunton PJ, Leng G, Russell JA (2010) Circulating secretin activates supraoptic nucleus oxytocin and vasopressin neurons via noradrenergic pathways in the rat .Endocrinology. 2010 Jun;151(6):2681-8.

Caquineau C, Douglas AJ, Leng G. (2010) Effects of cholecystokinin in the supraoptic nucleus and paraventricular nucleus are negatively modulated by leptin in 24-h fasted lean male rats. J Neuroendocrinol. 2010 May;22(5):446-52.



Leng G, Onaka T, Caquineau C, Sabatier N, Tobin VA, Takayanagi Y.(2008) Oxytocin and appetite. Prog Brain Res. 2008;170:137-51

Sabatier N, Rowe I, Leng G (2007) The role of intrahypothalamic release of oxytocin in the regulation of appetite. Bioch Soc Trans 35:1247-51

Onaka T Takayanagi, Y, Leng G (2010) Metabolic and stress-related roles of prolactin-releasing peptide Trends Endocrinol Metabol 21:287-93

Douglas AJ, Johnstone LE, Leng G (2007) Neuroendocrine mechanisms of change in food intake in pregnancy; A potential role for brain oxytocin. Physiol Behav 91:352-65.
StatusFinished
Effective start/end date1/05/0730/10/10

Funding

  • BBSRC: £453,311.00