Different Pathways and Different Purposes in Regulation Of The Energy Homeostasis
Date: October 26th, 2000
Title: The Hypothalamic Control of Energy Homeostasis: Different Pathways, Different Purposes
Speaker: Dr. Gareth Williams, University of Liverpool, Liverpool, U.K.
As a clinician who specializes in Endocrinology, Dr. Williams noted an increasing prevalence in non-insulin dependent diabetes (NIDDM) among the local population in Liverpool. As in other populations, obesity is an important cause, and this in turn is assumed to result from a combination of overeating and inactivity, in conjunction with a predisposing genetic background.
In order to gain better understanding into the neural circuits that govern energy balance, he has shifted his career focus towards research into the neuronal circuitry responsible for energy homeostasis. It is evident that some homeostatic processes must regulate body weight and fat mass.
Arcuate Nucleus and Neuropeptide Y stimulates hunger / eating.
The arcuate nucleus (ARC) of the hypothalamus appears to be a critical site at which energy fluxes are sensed within the brain. The blood-brain barrier in this region of the hypothalamus is modified to allow the entry of large peptides, such as leptin and insulin, which both reflect the status of body energy stores. The ARC contains populations of neuropeptide Y (NPY)-ergic neurons that project to the paraventricular nuclei (PVN) and dorsomedial nuclei (DMH) of the hypothalamus. These regions, in turn, are the focus of many integrative populations of nuclei, and thus coordinate inputs from populations of both feeding-stimulatory and inhibitory nuclei. NPY, one of the most abundant neuropeptides in the hypothalamic nuclei, is the most powerful feeding-stimulatory neural signal discovered to date. One interesting mechanism by which NPY stimulates feeding is by its ability to block peripheral satiety signals, such as cholecystokinin (CCK).
Orexins A and B also stimulate eating more
One class of the feeding-stimulatory peptidergic neurons that Dr. Williams has studied extensively is the orexins (A and B). The lateral hypothalamus (LH) contains orexin-ergic neurons, which are localized near particularly high densities of NPY-Y5 receptors. Orexin-expressing neurons may contribute to fasting-induced hyperphagia, as levels of orexin mRNA in the LH of rats double over basal in response to fasting. Administration of orexin-A to normal rats increases food intake, but tolerance develops, and therefore one cannot produce obesity from a chronic infusion of orexin-A (unlike the case with NPY, in which tolerance does not develop).
Orexins may also be the molecular signal underlying glucoprivic-induced food intake, since short-term (but not chronic) bouts of hypoglycemia increase orexin expression, and could thereby contribute to increasing food intake. By contrast, gastric distension (even minor) seems to prevent the increase in orexin expression normally induced by hypoglycemia. These orexin neurons also express the long form of the leptin-receptor (OB-R), and receive inputs from NPY- and AGRP- expressing neurons in the ARC. A system of leptin-regulated circuits, therefore, appears to integrate orexin-signaling with interactions among NPY-ergic ARC and PVN neuronal populations.
Orexins seem to act via two receptor types: OX1 is more specific for orexin-A, whereas OX2 recognizes both orexin-A and orexin-B. These receptors are widespread through many hypothalamic and extra-hypothalamic regions. They provide for differential regulation of the orexin signal. Fasting only upregulates expression of the OX1, and not the OX2, receptor.
Q. What’s the signal for energy loss that NPY responds to?
A. A fall in leptin and insulin levels, and undoubtedly other factors as well. When fat mass decreases, circulating leptin levels decrease accordingly. Since leptin inhibits NPY neurons, a fall in leptin results in an increase in NPY-ergic activity. There is evidence that loss of leptin inhibition is important in both underfeeding and in insulin-deficient (e.g. streptozocin-induced) diabetes; interestingly, studies by Alison Strack (Am J Physiol:1995; Jan:268:R142-9), prior to the discovery of leptin, suggested that most of the stimulation of NPY in these states could be explained by the fall in insulin and the rise in corticosterone (which stimulates hypothalamic NPY neurons).
Q. Is there an interaction between corticosterone levels and NPY activity?
A. There is some evidence that the feeding-stimulatory effects of the NPY-Y5 receptor may be altered by corticosterone. Also, as noted above, corticosterone per se appears to contribute to enhanced ARC NPY neuronal activity in fasting and in insulin-deficient diabetes.
Comment: Allison Strack has shown that a fall in both leptin and insulin will increase the effects of corticosterone on the Y5 receptor.
Q. Are all increases in feeding behavior and body weight observed in ob/ob or db/db rodents explained by enhanced NPY-mediated actions?
A. There is evidence in the literature to suggest that the hyperphagia in ob/ob mice is at least partly due to the loss of NPY inhibition by leptin, as NPY knockout superimposed on the ob/ob background reduces the hyperphagia; this involvement of NPY presumably also applies to db/db mice. Curiously, however, rodents that lack the gene encoding NPY (i.e. the NPY knock-out model) have normal weight and do not exhibit an increase in food intake. The ‘superficially’ normal phenotype of these mice suggests that other appetite-regulating systems are able to assume command if a key factor, such as NPY, is taken ‘out of service’.
Q. What is the role of NPY’s action in the diet-induced (DIO) obese animal model? Is it relevant?
A. Hyperphagia that is associated with the DIO model is not apparently mediated by NPY. We, and others, have found down-regulation of NPY mRNA in the ARC, together with up-regulation of Y5-like receptors in the perifornical region of the LH, which we have interpreted as reflecting reduced endogenous release of NPY in this crucial feeding-regulatory, and NPY-sensitive, site.
Q. So obesity induced by ‘voluntary’ hyperphagia and elevated consumption of dietary fat, as in palatable diets, is the result of dysfunction in some other neuronal population?
A. Potentially – this may relate to other mechanisms that are still poorly understood, such as reward, taste and smell. Individual variability in these systems may explain why only about 50% of animals become obese when they are exposed to a palatable diet.
Q. How does the DIO model relate to the actions of POMC?
A. This is an intriguing yet complex question, since POMC neurons produce both a-MSH (which inhibits feeding through the MC4-receptor) and b-endorphin (and other opioid peptides) that can stimulate feeding. Jo Harrold in our group finds evidence that the melanocortin system is an important determinant of whether or not unselected rats, exposed to palatable food, will go on to overeat and become obese. Those that resist overeating and gain the least weight show greater down-regulation of MC4-R in key hypothalamic nuclei, which suggests that there is greater activation of these receptors, and thus a more intense endogenous hypophagic drive. Intriguingly, this response appears to be programmed by an early rise in plasma leptin levels (within a few days of exposure to a palatable diet). We have data suggesting that the crucial event is not increased availability of a-MSH, but rather decreased availability of agouti-related peptide (AGRP), the endogenous inhibitor of the MC4-R. AGRP is released by the same ARC neurons that also produce NPY. This strengthens our view that these neurons are important gatekeepers of nutritional regulation, and are doing their best to respond to a wide range of signals indicating both under- and over-nutrition.