The Role Of The Lateral Hypothalamus In The Regulation Of Food Intake

Abstract

Obesity is a fast and wide-spreading condition that continues to be a major global health problem. Body Mass Index (BMI) which is a person’s weight (Kg) divided by their height (m) is used as a measure of obesity. An increase in BMI above the normal range increases an individual’s risk of mortality (1) and is also associated with an increased risk of developing number of co-morbidities such as coronary heart disease, type 2 diabetes mellitus and hypertension. Over the last century, the lateral hypothalamus (LH) has been implicated in the regulation of food intake but there is still uncertainty as to how it specifically affects it. To prevent obesity from becoming even more widespread, more research needs to be carried out to identify how the LH and other parts of the brain are regulating food intake. At the start of the 20 century, Frölich discovered a link between pituitary tumours and obesity based on clinical observations in patients with Frölich’s Syndrome (pituitary tumours associated with excessive subcutaneous fat and hypogonadism). However, there was debate as to whether injury to the pituitary gland or to the hypothalamus situated above the pituitary was the cause of the syndrome.(2). A later study by Aschner in 1912 which was carried out in dogs showed that removal of the pituitary gland without damaging the hypothalamus did not result in obesity, implying that damage to the hypothalamus is related to obesity (3). A series of experiments were than conducted in rats in 1940 by Hetherington and Ranson which confirmed this idea. They placed bilateral electrolytic lesions in the hypothalamus of rats without disrupting the pituitary. The found that all of the rats that had widespread bilateral damage to the region occupied by the dorsomedial and ventromedial hypothalamic nuclei, the arcuate nucleus and the fornix had doubled their body weight and had an enormous increase of extractable body lipids. They also incidentally discovered that lesions in the LH lead to a decrease in food intake.(4). Consequently, another study was carried out, this time by Anand and Brobeck in 1951. They wanted to build on Hetherington and Ransons’ discoveries to localise which areas in the hypothalamus, when destroyed or lesioned, would lead to a reduction/complete inhibition of food intake (hypophagia) and also the areas that would lead to an increase in food intake (hyperphagia) and thus obesity. They placed well localised, electrolytic lesions in the hypothalamuses of Sprague-Dawley rats and found that lateral hypothalamic lesions lead to aphagia, adipsia, a loss of body weight, starvation and in some subjects, death.(5) These effects brought about by lesions in the LH were then collectively termed as a lateral hypothalamic syndrome and proved that the LH has a major role in regulating food intake. In 1954, Stellar summarised all of the previous findings; he lesioned the ventromedial hypothalamic nuclei (VMH) which caused an increase in food intake and when electrically stimulated, a decrease in food intake was the result. He also lesioned the LH, causing a decrease in food intake and when electrically stimulated, an increase in food intake resulted. From these observations, the conclusion was made that the VMH is the satiety centre and the LH is the feeding centre (6). Thus the ‘dual-centre’ hypothesis was formed and this was the dominant theory in explaining the regulation of food intake for many decades. Naturally, the dual-centre hypothesis was challenged by many scientists over the following years. It was pointed out that the hypophagia caused by LH lesions was being caused by damage/interruption to the ascending nigrostriatal dopamine system passing in close proximity rather than to the LH itself. This resulted in a Parkinsonian syndrome and a significant reduction in nearly all movement and behaviour and hence a reduction in food intake (7)(8). It was observations like these that caused scientists to be uncertain The Role Of The Lateral Hypothalamus In The Regulation Of Food Intake 2 of 5 about the dual-centre model and the role of the LH in controlling food intake. Several years later, cell-specific lesion methods appeared, bringing the VMH and LH back into the spotlight. In a study conducted by Grossman in 1978, the LH was lesioned chemically with kainic acid without damage to the ascending dopaminergic system and resulted in hypophagia (9). This study reintroduced the idea that the LH was involved in feeding and was supported even further by neuroanatomical studies that displayed a lateral hypothalamic cell system which possessed direct projections to the cerebral cortex and to the autonomic and motor systems. The ascending and descending connections in this widespread lateral hypothalamic system predicted that it had the necessary anatomical range to support LH phagic function (10). This prediction was affirmed by the subsequent discovery of two new polypeptides in LH neurons; melanin concentrating hormone (MCH) (11) and the orexins (ORX) (12) which were found in separate, spatially overlapping neuronal populations in the perifornical region, LH area and zona incerta in the rodent and human brain (13). Both of the ORX and MCH cell groups contribute to the entire range of LH neuronal projections, from the cerebral cortex to the spinal cord.(11,13). These peptides were found to have an orexigenic function which further implicated the LH in having a critical role in food intake. A study by Qu et al. about the role of MCH in the central regulation of feeding behaviour reported that MCH augmented ongoing feeding, fasting stimulated MCH gene expression in the hypothalamus and MCH mRNA was raised in genetically obese ob/ob (leptin deficient) mice (14). Transgenic mice overexpressing precursor MCH have also been shown to be hyperphagic and develop centripetal obesity (15). ORX were discovered simultaneously by two groups of investigators, De Lecea et al.(16) and Sakurai et al.(12). It was initially observed that ORX’s effect on food intake were similar to that of MCH; it stimulated food intake when administered intracerebroventricularly (ICV) and its mRNA levels were increased by food deprivation (12). However, successive studies implied that the orexigenic effects of ORX were due to an increase in generalised behaviour arousal(17) as a deficiency in ORX or the ORX2 receptor in animals and humans is associated with narcolepsy(18,19). Even though the anatomical relationship between cells expressing MCH and ORX remained to be elucidated, there appeared to be at least two different signalling molecules which may be mediating LH-dependent food intake (13); MCH and ORX neurons may be regulating both cognitive and autonomic aspects of food intake (20). Prior to and during the discovery of MCH and ORX, other major findings had been made in the field of food intake regulation. Scientists were moving away from the theory that specific hypothalamic nuclei controlled satiety and feeding. They were starting to believe that energy homeostasis was being controlled by neuronal circuit systems which signalled using specific neuropeptides. Intensive research was being carried out to identify orexigenic and anorectic neurotransmitters in the hypothalamus, followed by identification of the neuronal sites of their production, release and the receptors on which they acted upon. There was also evidence showing the relationship between these neurotransmitter producing neurons and the fact that these neurons could coproduce more than one appetite-regulating signal (21,22). Through this research it was discovered that there were two primary populations of neurons within the arcuate nucleus (ARC) which amalgamate signals of nutritional status and influence energy homeostasis. One neuronal circuit stimulates food intake through the expression of the orexigenic factors, neuropeptide Y (NPY) (13) and agouti-related protein (AgRP) (23), while the other circuit inhibits food intake via the expression of the anorectic neuropeptides, pro-opiomelanocortin (POMC) and cocaineand amphetamine-regulated transcript (CART)(24). In a study by Elias et al. it was found in rat and human models that the orexigenic MCH and ORX neurons in the LH comprise distinct populations that receive innervation from the NPY/AgRP and a-MSH (the POMC gene product)/CART fibres from the ARC (20). Therefore it is significant to note that peripheral circulating factors acting on the inhibitory and stimulatory neuronal feeding circuits in the ARC (through the blood-brain barrier) have an effect further downstream on the MCH and ORX neurons of the LH which project to the entire neuraxis, including monosynaptic projections to several regions of the cerebral cortex, to alter the regulation of food intake. The position of the ARC in the brain is vital to its function; it is accessible to circulating signals of energy balance via the underlying median eminence as this part of the brain is not fully protected by the blood-brain barrier (25). Hence, peripheral signals (e.g. gut hormones, PYY and GLP-1) are able to cross the blood-brain barrier. This signifies the regulatory role of the blood-brain barrier in the passage of some circulating energy signals. Possibly one of the most important discoveries with regards The Role Of The Lateral Hypothalamus In The Regulation Of Food Intake 3 of 5 to food intake and energy homeostasis in the last two decades has to be that of leptin. Leptin is a satiety hormone that suppresses food intake and decreases body weight. It is produced by white adipose tissue and plays a crucial role in the maintenance of neuroendocrine and body weight homeostasis. (26). It acts as a marker of adipose stores in the body; therefore the more obese an individual is the more circulating leptin they will have. Cloning of the leptin gene and demonstration that leptin administration to ob/ob (leptin deficient) mice corrects obesity as well as neuroendocrine and autonomic abnormal