Question

Briefly outline the neuroendocrine pathways mediating “homeostatic” control of body weight, with particular emphasis on the neural and hormonal mechanisms by which the body signals metabolic cues to the brain.

Answer 1

Neuroendocrine pathways mediating control of body weight:

The brain plays a critical role in the regulation of physiological processes including energy homeostasis. Central nervous circuits instantly assess and integrate peripheral metabolic, endocrine and neuronal signals, and coordinate a response that modulates both behavioral patterns and peripheral metabolism according to acute and chronic requirements.

The brain directs, coordinates and integrates circulating hormones and metabolites that signal energy availability. As a consequence it modifies energy intake and expenditure to match energy demands on an ongoing homeostatic basis, establishing a metabolic “set-point”.

Changes in body weight reflect respective changes in energy balance resulting from an imbalance between energy taken up (food intake) and energy expended (for locomotor activity, basal metabolism, and thermogenesis). Therefore, any alterations in food intake or energy expenditure precede measurable alteration in body weight.

The main brain areas of homeostatic regulation:

Two of the major brain areas that play a key role in the homeostatic regulation of energy balance are

   hypothalamus (including the arcuate nucleus, ARC) and

   brainstem (including the nucleus tractus solitarus, NTS).

Both of these have strong connections to circumventricular organs (e.g. median eminence, area postrema) that lack a normal blood brain barrier or contain specialized transport systems to allow the direct access of peripheral signaling molecules, nutrients, metabolites and hormones that therefore cannot access other brain areas.

• The hypothalamus is considered the main integrator and processor of peripheral metabolic information especially for factors signaling medium-term to long-term changes in energy balance like leptin, insulin and ghrelin. This basal diencephalic area of the brain contains several nuclei (i.e. collection of neuronal cells) that have been shown in the past century to be key brain regions in the regulation of homeostasis. Depending on the metabolic status signal integration in hypothalamic nuclei mainly contributes to meal initiation .
• The brainstem on the other hand, integrates short-term signals, mainly originating from the gastrointestinal tract contributing to meal termination (e.g. cholecystokinine and neuronal input from vagal afferents.

Neurotransmitters:

GABA represents the main inhibitory neurotransmitter in the central nervous system (CNS)

Intracerebroventricular injections of GABA induce feeding and positive energy balance. GABA receptors were detected in hypothalamic regions that are important for the regulation of feeding.

A finely tuned balance of action potentials, synaptic neurotransmitters, feedback loops and neuropeptide expression levels between regulatory centers in the brainstem, hypothalamic nuclei, basal ganglia, nucleus accumbens and even the cortex underlies the constant adjustments that take place.

Homeostatic regulation of energy balance: connecting the hypothalamus, hindbrain and the gut.

Homeostatic regulation of energy balance requires the brain to maintain the appropriate energy levels by instantly modulating metabolites, fuel stores or hormone secretion. This demands first the ability of sensing metabolic and hormonal changes in the periphery by integrating the information from afferent signals projecting to the brain. Those signals include tissue-specific signaling molecules (e.g. leptin, ghrelin, cholecystokinin), metabolites (e.g. glucose, fatty acids), hormones (e.g. insulin, glucocorticoids, adrenaline, noradrenaline) or vegetative nerve terminals (e.g. vagal afferents).

Peptides secreted by the gastrointestinal tract during eating or digestion mainly act as satiety signals, conveying information on short-term changes in nutrient and energy supply, whereas factors secreted by other peripheral organs and tissues (e.g. adipose tissue, pancreas) rather serve to signal long-term changes in metabolic state or energy stores. In addition, hormones reflecting caloric intake and acute nutritional requirements complete the information flow to the brain.

Inside the brain, central nervous circuits coordinate a respective efferent response that modulates both behavioral patterns and peripheral metabolism according to acute and chronic requirements .

The classical endocrine axes, consisting of hypothalamic releasing hormones, pituitary hormones and peripheral endocrine signals are, without exception, involved in mediating efferent information and maintaining the balance of metabolism and energy homeostasis.