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NutrInsight • Satiety: News Insights
The hypothalamic circuit: homeostatic regulator
The hypothalamus is a small structure of the forebrain. It has been recognized for a long time as a homeostatic regulator of body weight by integrating the controls of food intake, satiety, and energy expenditure. It is now clear that internal state signals have access to various hypothalamic nuclei through multiple routes, including hormone receptors, metabolite sensors, and afferent neural pathways. Internal state information is further processed within the hypothalamus and then drives pituitary-endocrine and autonomic effectors through relatively well-defined output pathways. Modulation of these processes by behavioural and other motivational systems, such as the sleep/wake cycle, pregnancy, lactation, and stress/ alertness levels, is under investigation.
The relative stability of adult body weight is often used to illustrate the amazing precision of the putative homeostatic regulatory system. Clearly, it powerfully defends against nutritional deficits. By contrast, since there was no evolutionary pressure to develop a mechanism to defend the upper level of body adiposity, the power of the homeostatic mechanisms in the defence against energy surplus remains a matter of debate. While some experts argue that obesity can only be the result of a pathologically corrupt homeostatic regulator, others believe that the homeostatic regulator is just fine, but simply overwhelmed by the modern nutritional environment.
The arcuate nucleus of the hypothalamus is a site of convergence of central and peripheral signals. It contains distinct populations of neurons that are critically involved in the control of food intake. Orexigenic agouti- related protein (AgRP) neurons respond to circulating satiety and hunger signals, including glucose, leptin, insulin, and ghrelin. Research has shown that such neurons are essential for feeding in mice [Luquet et al., 2005]. A temporally controlled ablation of AgRP neurons after an injection of a specific toxin caused rapid starvation in adult mice. In contrast, their ablation in neonatal animals had minimal effects on feeding, suggesting that network-based compensatory mechanisms can develop after the ablation of AgRP neurons in neonates. While inhibition of AgRP neuronal activity in hungry mice reduces food intake, acute activation of AgRP neurons using a designer drug rapidly induced feeding, reduced energy expenditure, and ultimately increased body fat stores [Krashes et al., 2011]. Activating AgRP neurons drove intense food-seeking behaviour, demonstrating that AgRP neurons engage brain sites controlling multiple aspects of feeding behaviour [Krashes et al., 2011].
The cortico-limbic systems: cognitive and emotional brain
The omnipresence of conditioned food cues in the environment, the high obtainability of energy-dense foods, the minimal physical food procurement costs, and a sedentary lifestyle, predispose some individuals to overeating and weight gain in spite of the homeostatic regulator. Because many of these factors act through cognitive, emotional-affective, and executive functions of the brain, the discussion has shifted from the hypothalamus to include cortico-limbic systems, particularly those processing pleasure, reward, incentive motivation, satisfaction, delayed gratification, impulsivity, cost-benefit calculations, and conscious decision making.
Ingestive behaviour is much more than swallowing food. The appetitive phase of food procurement often demands complex cognitive processing. One of the crucial factors for human evolution was the tremendous expansion of the cerebral cortex. Areas of the cortex have specialized in functions that shape ingestive behaviours and allow them to respond to incoming signals from lower neural structures. The sensory representation of food, food reward, and expectancies about food are organized in the orbitofrontal cortex, the cingulate gyrus and the insulae. The executive control over food intake rests in the dorsolateral and prefrontal cortex areas. A corticolimbic neural network is involved in learning and maintaining representations of predictive food-related reward. In addition to input from hypothalamic sensors of fuel availability, corticolimbic areas are very likely to receive input from the gastro-intestinal tract via the vagus nerve and nucleus of the solitary tract.
Measuring neural activity is key to understand this complex system of the”metabolic” brain (hypothalamic circuit) and the “cognitive/emotional” brain (cortico-limbic systems).
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