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Metabolic homeostasis – an overview
In normal physiology, energy intake and utilization is perfectly balanced with the body’s energy needs. This is referred to as metabolic homeostasis. Upon digestion of food in the gastrointestinal tract, nutrients are sensed by the intestines, the pancreas and the brain. These organs then relay signals to the muscle, liver, fat and back to the brain to develop a proper coordinated response to achieve metabolic homeostasis, including when to end a meal, when to use the digested energy or when to take it up and store it.
Metabolic homeostasis is largely driven by the actions of hormones and neural activity. The pancreatic islets can sense the level of blood glucose levels. When glucose levels are low, such as during an overnight fast, glucagon is released. This hormone acts on the liver to promote hepatic glucose production so that other organs that rely solely on glucose as an energy source, such as the brain and kidney, have enough immediate energy to function properly.
Immediately after a meal, when blood glucose levels spike higher, the pancreas recognizes this occurrence and releases insulin in response. Insulin then acts primarily on the muscle to take up the dietary glucose and store it as glycogen. It also acts on the liver to take up the glucose, converting it into glycogen in that organ as well, though it can also signal so that glucose is converted into lipids. At the same time, insulin turns off endogenous hepatic glucose production. Insulin also acts on adipose tissue to take up excess glucose (what is not scavenged by the muscles and liver) and signals the cell to convert it into fat so it can be stored as an alternative energy supply in that tissue for future use. Likewise, insulin also inhibits lipolysis in the adipose tissue, ensuring further storage of fats. Fats can also come from the diet, where it is released by the gut in the form of chylomicrons. The chylomicrons are broken down by lipases on the surface of liver, muscle, and adipose cells and the liberated fatty acids are taken up by these organs and contributes to the pool of fats in these organs.
A critical tissue in metabolic regulation is the adipose tissue. In addition to being a key depot for energy storage, it is also a key endocrine organ. It releases a number of signaling hormones (referred to generically as adipokines), including leptin and adiponectin. Leptin acts on many different organs, including the brain via effects on food intake, to regulate whole-body metabolism. As leptin levels rise with increasing adiposity it is generally considered a long-term gauge of overall energy supply and thus is more a chronic effector of metabolism, whereas other hormones, such insulin, CCK, ghrelin, etc, are more acute effectors of metabolism. Another key adipokine is adiponectin, which also acts on many tissues to positively regulate whole-body well being. In addition to metabolic hormones the adipose tissue is also a key source of anti-inflammatory and pro-inflammatory hormones and cytokines.
Another key player in metabolic homeostasis is the gastrointestinal (GI) tract. Besides being the site of nutrient absorption, the GI tract also is the source of key hormones that act systemically to promote proper metabolism. Cholecystokinin (CCK) is released from the gut upon a meal and promotes digestion, but also acts on the nervous system to regulate central nutrient sensing as well as satiety. Other gut hormones, such as ghrelin, peptide YY (PYY), and endocannabinoids (ECs), also are released to regulate satiety via central effects. In addition, the gut also secretes incretins, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), which are hormones that stimulate insulin secretion and the potency of its signaling, inhibit glucagon release, and slow the motility of the GI tract, thus delaying the absorption of nutrients. Incretins can act even before the rise in blood glucose levels, so in a sense they prime the system.
In addition to hormones, the gut also hosts a microbiome of intestinal bacteria. Recent studies have shown the importance of this microbiome in maintaining proper metabolic homeostasis. Likewise, the immune system also plays an important role as nutrients, especially lipids, can regulate the activity of this system and affect its interplay with key metabolic organs and tissues.
Finally the brain plays a key role in maintaining proper metabolic homeostasis – both as an effector and a target of regulation. Satiety is composed of two parts: a homeostatic response, mostly regulated by the hypothalamus and nearby nuclei, that ensures that energy intake equals energy needs; and a hedonic response, mostly mediated by higher brain regions, that regulates mood and the pleasure of eating. The brain can also directly sense nutrient levels and act accordingly on the periphery via autonomic regulation. Part of this latter regulation is mediated by a hormonal relay system involving the hypothalamic-pituitary-thyroid (HPT) axis that leads to the release of thyroid hormones. These hormones can act directly on cells to increase basal metabolism by regulating gene activity, but also on the brain to increase peripheral metabolism via central relays of the sympathetic nervous system to the brown adipose tissue.