Ppars

PPAR-yl PPAR-y2

PPAR-ß, NUC-l, FAAR (fatty acid activated receptor)

Liver (main site); also kidney, heart, muscle, brown adipose tissue

Widespread

Widespread at low levels

Adipose tissue

Apolipoprotein AI; apolipoprotein AII; enzymes of peroxisomal fatty acid oxidation; liver FABP; CPT-1; enzymes of mitochondrial fatty acid oxidation

Not known although HDL concentrations increase with activation

Factors involved in adipocyte differentiation; adipose tissue FABP (also known as aP2); lipoprotein lipase; fatty acid transport protein; acyl-CoA synthase; GLUT4; phosphoenolpyruvate carboxykinase

Apolipoprotein CIII

Not known

Leptin

Based on information in Schoonjans, K., Staels, B. & Auwerx, J. (1996) Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. Journal of Lipid Research, 37, 907-925; Jump, D.B. & Clarke, S.D. (1999) Regulation of gene expression by dietary fat. Annual Review of Nutrition, 19, 63-90; Auwerx, J. (1999) PPARy, the ultimate thrifty gene. Diabetologia, 42,1033-1049; Clarke, S.D. (2000) Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance. British Journal of Nutrition, 83 (Supplement 1), S59-S66.

vention. A group of agonists of the PPAR-a receptor, known as fibric acid derivatives or fibrates, are useful drugs in the treatment of patients with elevated plasma triacylglycerol concentrations and low HDL-cholesterol concentrations. Their effects are apparently brought about by up-regulation of lipoprotein lipase and hepatic fatty acid oxidation, thus allowing the body to dispose of excess fatty acids, and also secretion of apolipoproteins AI and All, leading to increased HDL-cholesterol concentrations. More recently a new group of drugs, the thiazolidinediones or 'glitazones', have been developed, which appear to improve the sensitivity of the body to insulin. These are finding a place in the treatment of type 2 (maturity-onset) diabetes, which is usually associated with obesity and in which the ability of tissues to respond to insulin is reduced (Section 5.4.4). It has been discovered that the thiazolidinediones are potent agonists of PPAR-y in adipose tissue. How activation of PPAR-y in adipose tissue should lead to a widespread improvement in response to insulin is not clear, although it is interesting that an early effect of thiazolidinedione treatment is a reduction in the plasma concentration of non-esterified fatty acids.

5.3.3 Other nuclear receptors are activated by fatty acids and affect gene expression

It seems likely that new mechanisms for the regulation of gene expression by lipid-related

Fig. 5.15 The peroxisome proliferator activated receptor (PPAR) system and regulation of fatty acid disposition in liver and adipose tissue.

molecules will continue to be uncovered. One example is the nuclear receptor/transcription factor known as Hepatic Nuclear Factor-4a (HNF-4a). Fatty acyl-CoA esters appear to be an important natural ligand for HNF-4a, which in turn activates expression of a number of genes including apoli-poprotein CIII, and pyruvate kinase. It has been suggested that the down-regulation of apoCIII expression by PPAR-a is mediated by competition with HNF-4a.

5.3.4 Adipose tissue secretes hormones and other factors that may themselves play a role in regulation of fat storage

The role of white adipose tissue as an organ of triacylglycerol storage was described in Section 3.3.1. In recent years it has become clear that adipocytes are also active in secretion of a number of peptides and other compounds that may in turn help to regulate both lipid metabolism and other functions. Some of these are listed in Table 5.5. The hormone leptin is a protein of 167 amino acids. It was discovered in 1994 by positional cloning of the ob gene responsible for gross, spontaneous obesity in a mutant strain of laboratory mice. Only mice homozygous for the mutation (ob/ob mice) show the obese phenotype. Painstaking work from the laboratory of Jeffrey Friedman at Rockefeller University in New York led to the identification of the gene and the realization that it coded for a novel hormone, expressed almost exclusively in white adipose tissue. The hormone was called leptin (Greek leptos, thin). When purified recombinant leptin was injected into ob/ ob mice, they lost weight and became normal. The weight loss was the result of both decreased food intake, and increased energy expenditure. In normal animals, and humans, leptin secretion increases with increasing fat stores. Leptin receptors are widespread, and there are several isoforms produced by alternative splicing of transcripts from a single gene. A short, membrane-spanning form, believed to be responsible for leptin transport, is found in the choroid plexus, the brain region that governs transport of peptides between the bloodstream and the hypothalamus. In the hypothalamus itself, a brain region that controls many bodily functions including appetite and the activity of the autonomic nervous system, the long-form, signalling isoform of the leptin receptor is expressed. Leptin carries a signal from adipose tissue to the brain that the fat stores are growing and that it is appropriate to reduce food intake and increase energy expenditure. It also signals to other organs and tissues, and the widespread role of leptin in regulation of energy metabolism is now being discovered. One important role is that of a signal to the reproductive system that the fat stores are sufficient to support pregnancy and birth. Female and male ob/ob mice are sterile, and their fertility returns on treatment with recombinant leptin. This is probably the explanation also for the common observation that extreme thinness (arising, for instance, either from eating disorders or from regular physical training) is associated with amenorrhoea (absence of menstruation).

Although the main factor regulating leptin secretion from the adipocyte is cell size (i.e. tria-cylglycerol content), there is additional modulation by the short-term feeding state. This appears to be mediated largely by insulin, which acts through the adipocyte determination and differentiation factor-1, ADD-1 (or SREBP-1c), to increase leptin expression. Thus, leptin secretion increases on feeding (acting to reduce further food intake) and is

Potential role

Transport to endothelium; uptake of circulating triacylglycerol fatty acids.

Formation of C3a-desarg or acylation stimulating protein; stimulation of fatty acid storage.

Systemic participation in reverse cholesterol transport; adverse role in generation of atherogenic lipoprotein phenotype in obesity/ insulin resistance.

Lipoprotein metabolism.

Regulation of blood pressure (after conversion to angiotensin-II).

Hormone signalling size of fat stores, playing widespread role in metabolic regulation.

Increases coagulating ability of blood.

Coagulation pathway.

Cytokine, perhaps reducing fat storage; systemically, may reduce sensitivity to insulin (although there is some doubt about adipose tissue's contribution to systemic concentration).

Cytokine with role in inflammatory processes.

Probably local role in regulation of blood flow and lipolysis. Products of lipolysis; distribution to other tissues.

Table 5.5 Proteins and other factors secreted by adipocytes Secreted product Proteins

Lipoprotein lipase

Complement components D (adipsin), B, C3 Cholesteryl ester transfer protein

Apolipoprotein-E Angiotensinogen Leptin

Plasminogen activator inhibitor-1 (PAI-1) Tissue factor Tumour necrosis factor-a

Interleukin-6

Other factors

Prostaglandins PGE2 PGI2 (prostacyclin) Non-esterified fatty acids, glycerol

This tabulation is not exhaustive and is expanding all the time.

suppressed during fasting (so acting to increase food intake).

The leptin system also operates in humans, although it became clear soon after the discovery of leptin that the vast majority of obese humans have high, not low leptin concentrations in their circulation, just as appropriate for their enlarged fat stores. The message is that the majority of human obesity does not result from a failure of adipose tissue to secrete leptin, but from a failure of the brain to respond to it. The first clinical trials of recombinant leptin as a treatment for human obesity have recently been reported. Obese patients treated with high doses of leptin, by subcutaneous injection once a day, showed some weight loss, although it was not marked - perhaps not surprisingly in view of their 'leptin resistance'. However, we can be certain that the leptin system plays an important role in humans. A small number of families has been identified in which there are one or two individuals who have shown remarkable obesity from a very early age. Sequencing of the leptin gene has shown that these families carry a mutation rendering it ineffective, and that some of the rare cases of extreme precocious obesity are homozygous for this mutation or for a mutation in the leptin receptor. One pair of grossly obese cousins studied by Stephen O'Rahilly and his group at the Department of Medicine in Cambridge, UK, has displayed an almost incredible craving for food and failed ever to lose weight despite periods in hospital to try to restrain their eating. They are both homozygous for a particular frameshift mutation in the leptin gene. They have now been treated with recombinant human leptin, which has normalized their eating behaviour and led for the first time to weight loss. There appears to be little effect on energy expenditure, so in humans the leptin system probably regulates food intake more than energy expenditure. These may be rare accidents of nature, but they show that the leptin system is crucial for normal regulation of feeding in humans.

Other proteins secreted from adipocytes that have a role in lipid metabolism include lipoprotein lipase (secreted for transport to the capillary endothelium), apolipoprotein E (see Table 5.5) and cholesteryl ester transfer protein. Adipocytes also secrete a number of peptide components of the complement system, which is important in host defence against infection. It has recently been realized that these include the factors known as D, B and C3, all components of the alternative (as opposed to the classical) complement pathway. Factors D (also known as adipsin, to reflect its origin), B and C3 interact to produce a peptide of 76 amino acids that is known to immunologists as C3a-desarg (formed by removal of a C-terminal arginine from the fragment C3a). C3a turns out to be identical to a protein that had been identified by Allan Sniderman and Katherine Cianflone, of McGill University in Montreal, as a potent stimulator of fatty acid esterification in adipocytes and termed by them acylation stimulating protein (ASP, Section 3.6.2). Production of ASP by adipocytes is stimulated by the presence of chylomicrons. This suggests a co-ordinated system of regulation, whereby the arrival in adipose tissue capillaries of dietary fat in the form of chylomicron-triacylgly-cerol triggers ASP secretion, which in turn stimulates the storage of dietary fatty acids as adipocyte-triacylglycerol after their release from chylomicrons by lipoprotein lipase (Fig. 5.16).

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