Homeostasis And Organ Crosstalk

The ability of the organism to sense energy status and switch between demand for energy substrates in the fasted state and their storage in the postprandial state involves close communication between the organs involved in energy homeostasis, and integration of endocrine (hormones, adipocytokines, inflammatory cytokines), metabolic (glucose, FFAs, amino acids and intermediary metabolites), and neural signals. Liver, pancreas, brain, muscle, intestine, and adipose tissue are the major organs involved in co-ordination of energy metabolism. These organs are able to communicate with each other and to sense the energy status of the entire organism, thereby coordinating their function, but the precise mechanism of this communication remains poorly understood. Two examples illustrate this point. It is still not known, for example, how the healthy pancreas "senses" small variations in extrapancreatic tissue insulin sensitivity in the absence of a rise in blood glucose, to modify insulin secretion acutely and chronically, thereby maintaining normoglycemia (3). Likewise, it is not well understood how the silencing of a key regulator of glucose uptake, GLUT4, in one tissue such as skeletal muscle results in significant changes in insulin sensitivity and glucose uptake in another organ such as adipose tissue (4). The converse also appears to be true, where downregulation of GLUT4 and glucose transport selectively in adipose tissue has been shown to cause insulin resistance in muscle (5), perhaps by diverting FFAs and other fuels from adipose to nonadipose tissues. Plasma FFAs have long been implicated in mediating the cross talk among organs, and no doubt play an important role, but with the recent discovery of many additional modulators of insulin sensitivity and metabolic processes, it seems increasingly unlikely that a single factor is responsible for cross talk among organs. Instead, a complex array of metabolic, endocrine, and neural signals likely underlies the remarkable coordination of energy homeostasis.

The liver plays a pivotal and unique role in maintaining whole-body glucose and FFA homeostasis. It has the ability to either synthesize lipids via the de novo lipogenic pathway, or to use them for energy by mitochondrial ^-oxidation, depending on the energy status of the organism. In the fasting state, glucose is produced predominantly by the liver, by gluconeogenesis and glycogen breakdown (glycogenolysis), to ensure sufficient glucose supply to the central nervous system. Postprandially, insulin suppresses hepatic glucose production (HGP) by both direct and indirect mechanisms.

Insulin secreted by the pancreas plays a central role in the switch from postabsorptive (fasting) to postprandial metabolic response (6). Although insulin acts directly on hepatic insulin receptors to suppress hepatic glucose production (7), insulin-mediated reduction of FFA release from adipose tissue participates indirectly in the inhibition of HGP (8,9).

As discussed below in more detail, liver metabolism can be controlled "indirectly" by the brain, which plays a central integrative role as a "sensor" of the nutritional, hormonal, and neural status, integrating those stimuli to implement appropriate metabolic responses (10). Thus it appears that both direct and indirect effects of insulin are involved in the inhibition of HGP, although the relative contribution of the liver, brain and extrahepatic tissues remains an open question (7).

Skeletal muscle is responsible for a large part of total body glucose uptake (80-85% of peripheral glucose uptake) and its metabolism will be discussed in detail elsewhere in this book.

The intestine plays a role in organ cross-talk, not only by nutrient digestion and absorption, but also by producing signalling peptides (i.e., ghrelin, cholecystokinin.), which can alter appetite and food intake (11), as well as by secreting in a nutrient-dependent manner the incretins GLP-1 and GIP, peptides which stimulate insulin secretion in response to glucose, delay gastric emptying, inhibit glucagon secretion and inhibit apetite (12).

Adipose tissue is the largest energy storage organ in the body, storing energy in the form of triglycerides and mobilizing them by lipolysis, with release of fatty acids and glycerol into the circulation (13). Recently, however, there has been growing appreciation that adipose tissue is more than simply a fat storage and buffering compartment. It is an extremely active endocrine organ, playing an important role in signalling to muscle, liver, and central nervous system by secreting the so-called adipocytokines (leptin, resistin, adiponectin) and inflammatory mediators such as TNFa, IL-6, and PAI-1 (14).

FFAs as Signaling Molecules

Rossetti and collaborators have shown through an elegant set of in vivo studies in rodents that a sustained elevation of plasma FFAs induces a rise in the LCFA-acylCoA pool within the hypothalamus, which acts as a signal for nutrient availability, and which is sufficient to inhibit both food intake and hepatic glucose production (15,16). Central administration of oleic acid is able to mimic the effects of plasma FFAs on feeding behavior, and pharmacological intervention aimed at reducing intracellular LCFA-acylCoA abundance, either by blunting their synthesis or by favoring their oxidation, induces a derepression of food intake. Hypothalamic fat oxidation, as well as insulin infusion, suppresses HGP, an effect abolished by vagotomy (17). The role of elevated FFAs in the signal transmission has been further corroborated by experiments showing that inhibition of food intake by intraventricular administration of oleic acid is blunted by overfeeding in rats, indicating that impairment of the brain response to FFAs may have some deleterious consequences on food intake and consequently is likely to contribute to adiposity and associated insulin-resistance. AMP kinase (AMPK) is involved in the formation of malonylCoA via activation of ACC, thereby regulating the intracellular concentration of esterified LCFA. It is thought to act as a fuel sensor at the hypothalamic level, thereby inhibiting food intake (10,18). A feedback loop has been proposed in which both nutrients (such as FFAs and glucose) (17,19), and hormonal stimuli (such as leptin or insulin) (20), converge on the brain, which in turn limits nutrient ingestion and output from endogenous stores.

Supporting their role as signalling molecules, FFAs are able to modulate the activity of transcription factors involved in lipid and carbohydrate metabolism, thereby modifying the expression and/or activity of proteins involved in substrate uptake/transport, in enzymes of the different metabolic pathways, or in insulin signalling. Fatty acids are ligands for various nuclear receptors (PPARs, LXRs, or HNF-4a) and increase expression of some transcription factors such as SREBP1c and ChREBP, which are master regulators of de novo lipogenesis. Downstream effects of fatty acids on gene expression include increased liver, adipose, and intestinal FA transporters, increased glucose transporters, and esterifying/trapping FA enzyme acylCoA synthase, and they can more generally modulate metabolic pathways such as FA ^-oxidation, lipogenesis, or gluconeogenesis by acting on key rate-limiting steps involved therein (21).

From these data, fatty acids appear to act as important signalling molecules in energy homeostasis, and altered FFA metabolism may therefore have critical and deleterious consequences for whole-body fuel utilization and/or storage. Indeed, disorders of either fat storage or mobilization (leading to elevated plasma FFAs) are central in the pathogenesis of many of the metabolic features of the insulin resistance syndrome and type 2 diabetes. We will discuss the consequences of these abnormalities for hepatic glucose production, insulin action in muscle and liver, insulin clearance, and pancreatic ^-cell function, and examine strategies for reducing FFAs and their physiological consequences.


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    What organs involve in sugar metabolism?
    4 years ago

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