Explain Regulation of Metabolism?

In This Post, We Will Discuss About Regulation of Metabolism & Also Some Other Topics Like Regulation of metabolism Slideshare, Regulation of metabolism in plants, Hormonal regulation of metabolism, Types of metabolism.

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The control of fat storage and mobilization has been marked by the identification of a number of regulatory mechanisms in the last few decades. Isotopic tracer studies have clearly shown that lipids are continuously being mobilized and renewed even in individuals in energy balance. Fatty acid esterification and triglyceride hydrolysis take place continuously.

The half-life of depot lipids in rodents is about 8 days, meaning that almost 10% of the fatty acid stored in adipose tissue is replaced daily by new fatty acids. The balance between lipid loss and accretion determines the net outcome on energy homeostasis.

The synthesis of triglycerides, also termed lipogenesis, requires a supply of fatty acids and glycerol. The main sources of fatty acids are the liver and the small intestine. Fatty acids are esterified with glycerol phosphate in the liver to produce triglycerides. Since triglycerides are bulky polar molecules that do not cross cell membranes well, they must be hydrolyzed to fatty acids and glycerol before entering fat cells. Serum very-low-density lipoproteins (VLDLs) are the major form in which triacylglycerols are carried from the liver to WAT. Short-chain fatty acids (16 carbons or less) can be absorbed from the gastrointestinal tract and carried in chylomicron directly to the adipocyte.

Inside fat cells, glycerol is mainly synthesized from glucose. In WAT, fatty acids can be synthesized from several precursors, such as glucose, lactate, and certain amino acids, with glucose being quantitatively the most important in humans. In the case of glucose, GLUT4, the principal glucose transporter of adipocytes, controls the entry of the substrate into the adipocyte. Insulin is known to stimulate glucose transport by promoting GLUT4 recruitment as well as increasing its activity. Inside the adipocyte, glucose is initially phosphorylated and then metabolized both in the cytosol and in the mitochondria to produce cytosolic acetyl-CoA with the flux being influenced by phosphofructokinase and pyruvate dehydrogenase.

Glycerol does not readily enter the adipocyte, but the membrane-permeable fatty acids do. Once inside the fat cells, fatty acids are re-esterified with glycerol phosphate to yield triglycerides. Lipogenesis is favored by insulin, which activates pyruvate kinase, pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase. When excess nutrients are available insulin decreases acetyl-CoA entry into the tricarboxylic acid cycle while directing it towards fat synthesis. This insulin effect is antagonized by growth hormone.

The gut hormones glucagon-like peptide 1 and gastric inhibitory peptide also increase fatty acid synthesis, while glucagon and catecholamines inactivate acetyl-CoA carboxylase, thus decreasing the rate of fatty acid synthesis. The release of glycerol and free fatty acids by
lipolysis plays a critical role in the ability of the organism to provide energy from triglyceride stores. In this sense, the processes of lipolysis and lipogenesis are crucial for the attainment of body weight control. For this purpose, adipocytes are equipped
with well-developed enzymatic machinery, together with a number of non secreted proteins
and binding factors directly involved in the regulation of lipid metabolism.

The hydrolysis of triglycerides from circulating VLDL and chylomicrons is catalyzed by lipoprotein lipase (LPL). This rate-limiting step plays an important role in directing fat partitioning. Although LPL controls fatty acid entry into adipocytes, the fat mass has been shown to be preserved by endogenous synthesis. From observations made in patients with total LPL deficiency, it can also be concluded that fat deposition can take place in the absence of LPL. A further key enzyme catalyzing a rate-limiting step of lipolysis is HSL (hormone-sensitive lipase), which cleaves triacylglycerol to yield glycerol and fatty acids. Some fatty acids are re-esterified so that the fatty acid: The glycerol ratio leaving the cell is usually less than the
theoretical 3:1.

Increased concentrations of cAMP activate HSL as well as promote its movement from the cytosol to the lipid droplet surface. Catecholamines and glucagon are known inducers of the lipolytic activity, while the stimulation of lipolysis is attenuated by adenosine and prostaglandin E2. Interestingly, HSL deficiency leads to male sterility and adipocyte hypertrophy, but not to obesity, with an unaltered basal lipolytic activity suggesting that
other lipases may also play a relevant role in fat mobilization.

Hydrolysis in the basal state. The phosphorylation of perilipin following adrenergic stimulation or other hormonal inputs induces a structural change of the lipid droplet that allows the hydrolysis of triglycerides. After hormonal stimulation, HSL and perilipin are phosphorylated and HSL translocates to the lipid droplet. ALBP also termed aP2, then binds to the N-terminal region of HSL, preventing fatty acid inhibition of the enzyme’s hydrolytic activity.

The function of CETP is to promote the exchange of cholesterol esters of triglycerides between plasma lipoproteins. Fasting, high-cholesterol diets as well as insulin stimulate CETP synthesis and secretion in WAT. In plasma, CETP participates in the modulation of reverse cholesterol transport by facilitating the transfer of cholesterol esters from high-density lipoprotein (HDL) to triglyceride-rich apoB-containing lipoproteins. VLDLs, in particular, are converted to low-density lipoproteins (LDLs), which are subjected to hepatic clearance by the apoB/E receptor system. Adipose tissue probably represents one of the major sources of CETP in humans.

Therefore, WAT represents a cholesterol storage organ,
whereby peripheral cholesterol is taken up by HDL particles, acting as cholesterol efflux acceptors, and is returned for hepatic excretion. In obesity, the activity and protein mass of circulating CETP are increased showing a negative correlation with HDL concentrations at the same time as a positive correlation with fasting glycemia and insulinemia suggesting a potential link with insulin resistance.

Synthesis and secretion of RBP by adipocytes is induced by retinoic acid and shows that WAT plays an important role in retinoid storage and metabolism. In fact, RBP mRNA is one of the most abundant transcripts present in both rodent and human adipose tissue. Hepatic and renal tissues have been regarded as the main sites of RBP production, while the quantitative and physiological significance of the WAT contribution remains to be fully elucidated.

The processes participating in the control of energy balance, as well as the intermediary lipid and carbohydrate metabolism, are intricately linked by neurohumoral mediators. The coordination of the implicated molecular and biochemical pathways underlie, at least in part, the large number of intracellular and secreted proteins produced by WAT with autocrine, paracrine, and endocrine effects. The finding that WAT secretes a plethora of pleiotropic adipokines at the same time as expressing receptors for a huge range of compounds has led to the development of new insights into the functions of adipose tissue at both the basic and clinical level.

At this early juncture in the course of adipose tissue research, much has been discovered. However, a great deal more remains to be learned about its physiology and clinical relevance. Given the adipocyte’s versatile and ever-expanding list of secretory proteins, additional and unexpected discoveries are sure to emerge. The growth, cellular composition, and gene expression pattern of adipose tissue is under the regulation of a large selection of central mechanisms and local effectors. The exact nature and control of this complex cross-talk has not been fully elucidated and represents an exciting research topic.

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