Central and peripheral regulation of food intake and physical activity: pathways and genes

Abstract

A changing environment and lifestyle on the background of evolutionary engraved and perinatally imprinted physiological response patterns is the foremost explanation for the current obesity epidemic. However, it is not clear what the mechanisms are by which the modern environment overrides the physiological controls of appetite and homeostatic body-weight regulation. Food intake and energy expenditure are controlled by complex, redundant, and distributed neural systems involving thousands of genes and reflecting the fundamental biological importance of adequate nutrient supply and energy balance. There has been much progress in identifying the important role of hypothalamus and caudal brainstem in the various hormonal and neural mechanisms by which the brain informs itself about availability of ingested and stored nutrients and, in turn, generates behavioral, autonomic, and endocrine output. Some of the genes involved in this "homeostatic" regulator are crucial for energy balance as manifested in the well-known monogenic obesity models. However, it can be clearly demonstrated that much larger portions of the nervous system of animals and humans, including the cortex, basal ganglia, and the limbic system, are concerned with the procurement of food as a basic and evolutionarily conserved survival mechanism to defend the lower limits of adiposity. By forming representations and reward expectancies through processes of learning and memory, these systems evolved to engage powerful emotions for guaranteed supply with, and ingestion of, beneficial foods from a sparse and often hostile environment. They are now simply overwhelmed with an abundance of food and food cues no longer contested by predators and interrupted by famines. The anatomy, chemistry, and functions of these elaborate neural systems and their interactions with the "homeostatic" regulator in the hypothalamus are poorly understood, and many of the genes involved are either unknown or not well characterized. This is regrettable because these systems are directly and primarily involved in the interactions of the modern environment and lifestyle with the human body. They are no less "physiological" than metabolic-regulatory mechanisms that have attracted most of the research during the past 15 years.

Figure 1

Major mechanisms and factors determining energy balance.

Figure 2

Highly schematic diagram showing major components and flow of information of the peripheral and central systems involved in energy balance, regulation, and control of food intake. CNS, central nervous system.

Figure 3

Nutrient sensing in the alimentary canal and the control of food intake. Simplified schematic diagram showing the major pre- and postabsorptive transduction sites and mechanisms for the detection of ingested food and its macronutrient components. Nutrient information is sent to the brain through vagal and taste afferents (heavy dotted lines) or through the blood circulation (full lines). Specific receptors expressed by vagal afferent neurons are shown in rectangular boxes. Specific sensor mechanisms demonstrated for glucose, amino acids/proteins, and lipids/fatty acids are shown by gray, striped, and white squares, respectively. CCK, cholecystokinin; GHS-R, ghrelin receptor; GLP-1, glucagon-like peptide-1; IL-1, interleukin-1; PYY, peptide YY; TNF-α, tumor necrosis factor-α.

Figure 4

Hypothalamic peptidergic circuitry related to feeding and energy balance. Highly simplified diagram showing the two known neuron populations in the arcuate nucleus sensitive to signals of fuel availability and their projections to other key neuron populations orchestrating the adaptive behavioral, autonomic, and endocrine responses. CART, cocaine- and amphetamine-regulated transcript; CRH, corticotropin-releasing hormone; GABA, γ-aminobutyric acid; MCH, melanin concentrating hormone; α-MSH, α-melanocyte-stimulating hormone; PVN, paraventricular nucleus.

Figure 5

Molecular mechanisms of integration of various signals by hypothetical “nutrient-sensing neurons” in the mediobasal hypothalamus. AMPK, adenosine monophosphate-activated kinase; ATP, adenosine triphosphate; GABA, γ-aminobutyric acid; mTOR, mammalian target of rapamycin.

Figure 6

Highly simplified schematic diagram showing the multiple neural systems and pathways controlling food intake, energy expenditure, and energy balance, with emphasis on interactions between “metabolic,” “cognitive,” and “rewarding” brain systems.