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How was the Hypothalamus Identified as the 'Hunger Centre'?

The hypothalamus is the body's 'control centre', playing a role in many physiological functions. eg. motor functions, emotions, endocrine functions and food and water intake. It is an organ essential for maintaining the body's homeostasis by receiving information about the state of the body and making compensatory changes if needed by stimulating the release of various hormones. It is located in the middle of the base of the brain (see Figure 1) where it works in concert with the pituitary gland, acting as a neuroendocrine organ. The hypothalamus secretes various releasing hormones into the local blood capillaries which connect to the pituitary gland. These hormones then stimulate the release of the effector hormones into the bloodstream from the pituitary gland.

Figure 1: Illustrates the position of the hypothalamus in the human brain. The pituitary gland is located underneath the hypothalamus and they communicate through a network of portal blood vessels

Location of the hypothalamus in the human brain

 

Although it is well established now that the physiological functions mentioned above are under the control of the hypothalamus, it took many years before this was confirmed. At the beginning of the 20th century, behaviours such as eating and drinking were thought to stem from reflex actions. It took an American psychologist and intricate lesion experiments to show otherwise.

How was the role of the brain identified?

Appetite and the control of food intake were first thought to be controlled by a reflex action, originating peripherally in the stomach. In 1927 the American physiologist Walter Cannon, proposed that hunger signals came from the stomach as a ‘hunger pang’.  This pang caused feeding and so the impetus to eat came from a peripheral signal. At that time, peripheral control was thought to govern in other behaviours as well like reproductive behaviour.  The idea that appetite and feeding were governed somehow by the brain and not purely down to this form of reflex action occurred later, when in 1938, an American psychologist and behaviourist, Karl Lashley, most famous for his research into learning and memory, studied the theory of motivation.  Lashley first proposed the idea of the brain being the hunger centre.  His aim was to show that appetite and food intake were part of a group of behaviours controlled by motivation and that somewhere there must be a neural control centre for these behaviours. He thought this control centre was in the the brain and it acted to arouse or stop the motivation.  This mechanism involved hormonal signals as well as the internal and external environment.  His theory was not given the credit it deserved due to the continuing indecision regarding the source of the motivational signal, be it peripherally as thought by Cannon or centrally as now proposed by Lashley.  Almost another 20 years passed before a member of Lashley’s laboratory, Stellar (1954), identified the hypothalamus as the source of motivational behaviours like appetite.  

A series of intricate lesion experiments on the hypothalamus were carried out to find out what its precise roles were in appetite and the control of food intake.  These experiments found that the lateral hypothalamus was the ‘feeding centre’ as lesions to that caused a decrease in food intake and the medial hypothalamus was found to be the ‘satiety centre’ as lesioning it produced a marked increase in food intake (see Brobeck, (1946) for review of discovery).  These initial lesion experiments may seem rather crude now but those experiments provided the foundations onto which our knowledge has been built.

Figure 2:  The hypothalamic nuclei involved in regulation of appetite

Hypothalamic brain areas involved in appetite

The hypothalamus was therefore considered the prime candidate in appetite control but, through the excitement, attention focused away from the signalling mechanisms responsible for relaying information to and from the hypothalamus until many years later. 

How was the role of a circulating factor in appetite regulation first discovered?

The role of the brain in feeding behaviour had been established but questions still remained as to how the hypothalamus received information about the sensations of hunger and satiety ie. how much fat had been stored.  The discovery of a strain of mice spontaneously deficient in a single gene ‘ob’ resulted in the discovery of a circulating factor involved in the control of appetite.  The ob/ob mice were morbidly obese, insulin resistant, infertile and lethargic (Ingalls et al, 1950).

Figure 3:  An obese mouse deficient in the ob gene (left) next to a wildtype litter mate

ob/ob mouse and litter mate

 

The role of such a circulating factor was first proposed in 1953 by the biologist, Kennedy.  He investigated feeding behaviour in rats and found that even during periods of excessive eating, the levels of fat in food appeared to limit feeding.  There seemed to be a chemosensitive mechanism that balanced energy intake, the negative feedback signal seeming to come from adiposity.  This idea was known as the lipostatic theory, which at that time was just one of three theories including the glucostatic and body temperature theory. The lipostatic theory was not confirmed until 1973 when Douglas Coleman, a biochemist, using the intricate and extremely elegant method of parabiosis provided evidence of a circulating lipostatic factor. 

Coleman had found another obese mouse that he found to have a different genetic mutation from the the ob/ob mouse. He found this new mutant mouse to be obese and diabetic and so it was given the name db/db. He used parabiosis as he wanted to find out if a normal mouse had something that would help the db/db mouse and if there was something in the db/db mouse that could cause obesity.

When the parabiont pair consisted of a ob/ob mouse and a wildtype mouse, (see Figure 4A) the obese partner lost weight. When a normal mouse was crossed with a db/db mouse (Figure 4B), the normal mouse died from starvation.  When an obese mouse was crossed with a db/db mouse (Figure 4C) they could co exist quite happily with the ob mouse losing weight.  It was concluded that the db mice appeared to have a circulating factor that caused the obese and normal mice to stop eating, whilst they remained resistant to it.  When an obese mouse is joined with the a normal mouse, the obese mouse received this circulating factor from the normal mouse and so appeared to lose weight due to a decrease in appetite, they on the other hand, appear to have insufficient levels of this factor to affect the normal mouse.  In summary the db mice circulate a factor that their satiety centre is not responding to (due to a defective receptor) whilst the obese mice appear to have a normal satiety centre but produce insufficient (or no) levels of the satiety signal.    It was becoming clear that complex molecular mechanisms existed that were involved in appetite regulation. 

Figure 4: Parabiosis experiment showing the affects of leptin

examples of the parabiosis experiments investigating the role of leptin

Coleman’s experiment was not given the full credit it deserved as obesity was still thought to result from a behavioural problem, rather than a problem associated with genetics. Little more was done until the advancement of genetic techniques allowed this elusive satiety molecule to be determined, and in 1994 Jeffrey Friedman, using the ob/ob mouse strain revealed Leptin, a signalling molecule secreted from the adipocyte. This discovery revealed the adipocyte to not just be a lowly fat storage molecule, but an active member involved in controlling energy levels.

This leads our discussion onto the adipocyte cell.

Key references

Brobeck JR. 1946. Physiological Reviews. 25. pp541-559 - Excellent review of lesion experiments conducted on the hypothalamus and the various theories that were proposed to control food intake. (not available electronically)

Stellar E. 1989. Long term Perspectives on the Study of Eating Behaviour. Annals of the New York Academy of Sciences. 575. pp478 - a comprehensive history of the experiments performed to identify the hypothalamus as the centre governing the control of appetite.

 

 

 
   
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