Glucostatic theory of appetite control

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In the early twentieth century, a link was first made between blood glucose and appetite that led to the glucostatic theory of appetite control. In 1916, Carlson had suggested that plasma concentrations of glucose could serve as a signal for both meal initiation (low levels) and meal termination (high levels) (Mobbs, 2005). But it was not until the 1950's that Mayer put forward the glucostatic hypothesis. Originally it was thought that a rise in plasma glucose, for example after a meal, was sensed by neurons in the hypothalamus. These neurons which included “glucoreceptors” then signalled for meal termination. Glucose was thus thought of as a satiety factor (Flint, 2006).

This theory has been debated for many years. While many studies appear to support Mayer’s hypothesis, many others do not, and compelling evidence has yet to be found. The theory, which was popular in the 1950s, was losing support by the 1980s. At this time, scientists were beginning to think that the control of appetite was a more complex mechanism that would have to depend on the integration of a number of signalling pathways. The glucostatic theory was not abandoned altogether, as it was still thought to be important for short-term appetite control, but newly discovered peptides such as leptin became more likely candidates for long-term control.

Title of Subpart 1

Glucose homeostasis must be finely regulated by the absorption of food and the flow of recently stored energy substances through different metabolic pathways. Especially for brain glucose, it has to be supplied continuously from the blood stream since there is no storage for sugar available in the brain. It is known that changes in glucose level elicit complex neuroendocrine responses that restore blood sugar levels to the optimum range. (Ritter, S. et al. 2006) It is traditionally believed that different regions of the forebrain; particularly the hypothalamus and the brain stem have important centres which are responsible for monitoring blood glucose level and regulating feeding. (Mayer, J. 1955) However, Ritter R. G. et al. claimed that glucoreceptor cells are located in the hindbrain. This means that the glucose sensing cells have direct access to the central nervous system and could elicit immediate responses to retain the physiological norm. (Ritter, R. C. et al. 1981)　They also explained that the catecholamine neurons in the hindbrain help mediating responses to glucose deficiency by linking glucoreceptor cells to forebrain and spinal neurons. This enables us to stimulate behavioural and hormonal responses that elevate blood sugar level. These include increased food intake, adrenal medullary secretion, corticosterone secretion and suppression of estrous cycles. Complex behaviours involved in activities such as detection and identification of food are mainly regulated by the forebrain. Her studies suggest that the hind brain mediates the motivation for these activities via the neuronal circuit activated by some of the glucose sensing cells. They hypothesized that the signals detected by the glucoceptors are projected to the hypothalamus via norepinephrine and epinephrine neurons in the hind brain. This motivation circuit would have engaged the physical sign of energy deficiency with these behaviours. (Ritter, S. et al. 2006)　

The role of insulin and ghrelin in the glucostatic theory

It has been proposed that both ghrelin and insulin play important roles in appetite, hunger and the glucostatic hypothesis. However, studies have produced conflicting results and how these peptides relate to the glucostatic theory still remains unclear.

Insulin

Insulin, a peptide hormone, is required by cells in order to take up and use glucose from the blood. Studies have shown that insulin is correlated with satiety and food intake. It was found that in the short-term insulin is involved in limiting postprandial appetite (Flint, 2006). However, glycaemic responses appear to be more important for this. Another study found that in obese and overweight women serum insulin levels were negatively correlated with subjects hunger ratings. They were also positively correlated to fullness. Again it was found that glucose had a bigger part to play in this than insulin. Both these studies suggest that, although other factors appear to be important, insulin may play a role in appetite control.

Conversely, other studies have found no relationship between insulin and appetite. Because of this, it is uncertain how important insulin is in the control of appetite.

Ghrelin

It is now commonly accepted that ghrelin, a peptide produced in the stomach, stimulates appetite. It has been proposed that this peptide is involved in glucostatic signalling. Ghrelin levels peak before a meal or when a meal is expected. In rats it has been found that insulin-induced hypoglycaemia up regulates ghrelin mRNA expression. Ghrelin secretion is also inhibited by high glucose levels. This suggests that the cells which secrete ghrelin may be sensitive to changes in plasma glucose. This mechanism may play an important role in regulating energy metabolism.

When ghrelin is deleted, blood glucose is reduced and insulin levels are increased. This loss of ghrelin increases the ability of insulin to suppress glucose production. These findings show that ghrelin is important for glucose homeostasis. However, in a study by Sun et al. it was found that these effects were not related to changes in food intake or weight. As with insulin, there is little conclusive evidence suggesting an important role for ghrelin in the glucostatic hypothesis. There are, however, some studies have shown links between the two.

The Long-Term Control of Feeding and Energy Balance

The glucostatic hypothesis represents a physiological control system that fits the criteria for controlling short-term energy consumption. In contrast, the long-term control of feeding occurs via a different mechanism involving the secretion of a hormone Leptin, from fat (adipose) tissue, and its action on the central nervous system. The effects of leptin were first discovered in the 1950’s, although leptin itself was not discovered until 1994. The concentration of leptin in the circulation is proportional to the amount of fat in the body, and it alters body weight by either inhibiting the intake of food or by triggering hyperphagia. Once secreted, Leptin crossed the blood-brain-barrier via a receptor-mediated transport system (Wayne et al 2005). Its receptors are highly expressed in the hypothalamus and brain stem nuclei; these are both areas that are known to control feeding and energy balance. The binding of Leptin to these receptors influences the peptide systems, Pro-opiodmelanocortin (POMC) and Neuropeptide Y (NPY). POMC neurons in the arcuate nucleus produce the peptide alpha-MSH, an appetite suppressant. NPY is a potent feeding stimulant. An increase in leptin levels inhibits peptides, such as NYP, and causes an increase in alpha-MSH, therefore causing a decrease in feeding and regulating the long-term control of energy balance (Ahima & Osei 2004).

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