Human fat cell lipolysis: Biochemistry, regulation and clinical role

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 19, No. 4, pp. 471–482, 2005 doi:10.1016/j.beem.2005.07.004 available online at http://www.sciencedirect.com

1 Human fat cell lipolysis: Biochemistry, regulation and clinical role Peter Arner*

PhD, MD

Professor Department of Medicine M63, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden

Release of fatty acids (FAs) from adipose tissue through lipolysis in fat cells is a key event in many processes. FAs are not only energy substrates but also signalling molecules and substrates for lipoprotein production by the liver. Fat cells consist ofO95% triglycerides that are hydrolysed during lipolysis to glycerol and FAs. The major rate-limiting factor for lipolysis is hormonesensitive lipase, but additional lipases such as adipose tissue triglyceride lipase may also play a role. The regulation of human fat cell lipolysis is, in many ways, species unique. Only catecholamines, insulin and natriuretic peptides have pronounced acute effects. Catecholamines influence lipolysis through four different adrenoceptor subtypes, in contrast to rodents where only one subtype (b3) is of major importance. There are regional variations in adipocyte lipolysis leading to more release of FAs from the visceral than subcutaneous adipose tissue during hormone stimulation (insulin, catecholamines). Since, only visceral fat is linked to the liver (by the portal vein), alterations in visceral adipocyte tissue lipolysis have direct effects on the liver through portal FA release. The regional variations in lipolysis are further enhanced in obesity and polycystic ovarian syndrome, and are of importance for dyslipidaemia, hyperinsulinaemia and glucose intolerance in these conditions. There is a marked elevation of circulating FA levels among the obese, which may be due to enhanced production of tumour necrosis factor alpha in adipose tissue. This cytokine stimulates lipolysis through so-called MAP kinases. Pharmacological agents in clinical practice such as nicotinic acid and glitazones exert lipid-lowering and glucose-lowering effects, respectively, by decreasing FA output from the adipose tissue. This review covers the biochemistry, regulation and clinical aspects of human fat cell lipolysis. Key words: fat cell; adipose region; catecholamines; insulin; natriuretic peptides; tumour nectrosis factor alpha; gene polymorphism; obesity; polycystic ovarian syndrome.

Breakdown of triglycerides in adipocytes (lipolysis) resulting in the release of glycerol and non-esterified fatty acids (FAs) from adipose tissue is important for the regulation * Tel.: C46 8 5858 2342; fax: C46 8 5858 2407. E-mail address: [email protected].

1521-690X/$ - see front matter Q 2005 Published by Elsevier Ltd.

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of energy homeostasis.1 As well as being energy substrates, FAs have other important roles.2–4 They are transported in the circulation, bound to albumin, to other organs where they influence insulin action and glucose metabolism (muscle and liver), alter gene function as transcription factors (various tissues), are substrates for apolipoprotein production (liver) and regulate insulin production (pancreas). This chapter will focus on the biochemical, regulatory and clinical aspects on adipocyte lipolysis. Due to the clinical focus, special attention will be paid to lipolysis in humans. For the same reason, only white fat cells are discussed because brown fat depots nearly disappear in adult humans. In the interests of space, review articles rather than original articles will be utilized whenever possible. A PubMed search on ‘adipocyte or adipose tissue and lipolysis’ gavez4000 hits.

BIOCHEMISTRY OF LIPOLYSIS Fat droplets, which constituteO95% of the total adipocyte volume, are composed mainly of triglycerides. Triglycerides are step-wise broken down to diglycerides, monoglycerides and glycerol and FAs (Figure 1). This process is usually complete, meaning that one molecule of glycerol and three molecules of FAs are produced by CATECHOLAMINES

NATRIURETIC PEPTIDES

INSULIN β1

2A

β3 NPRA

IRS-1 IR

β2

Gi

PI3K

Gs

IRS-2 AC

PDE-3 5´-AMP

GC

cAMP

cGMP

PKA

PKG

TNFα p44/42 TNFR-1

PLIN ATGL

HSL

TG

DG FA

JNK

MGL

Glycerol

MG FA

FA

Figure 1. Regulation of lipolysis in human fat cells. b1,2,3, beta1,2,3-adrenergic receptors; a2A, a2A-adrenergic receptor, Gi,s, inhibitory (i) or stimulatory (s) G-proteins; AC, adenylate cyclase; cAMP, cyclic AMP; cGMP, cyclic GMP, NPRA, natriuretic peptide receptor A; GC, guanylyl cyclase; PKG, cGMP-dependent protein kinase; PKA, protein kinase A; TNFa, tumour necrosis factor alpha; P44/42 and JNK, MAP kinase pathways; TNFR1, TNFa receptor 1; ATGL, adipose-tissue-specific triglyceride lipase; HSL, hormone-sensitive lipase; MGL, monoglyceride lipase; TG, triglycerides; DG, diglyceride; MG, monoglyceride; FA, fatty acid; IR, insulin receptor; IRS-1,2, insulin receptor substrates 1 and 2; Pl3K, phosphadilyl inositol 3 kinase; PDE3, phosphodiesterase 3.

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the hydrolysis of one molecule of triglyceride. However, the release of FAs and glycerol from fat cells does not occur in the ratio of 3:1 because some FAs are re-utilized by the fat cells, mostly as re-esterification to new triglycerides.5 Very small amounts of glycerol are re-utilized because fat cells contain little glycerol kinase. The latter enzyme is rate limiting for glycerol metabolism. Insignificant oxidation of FAs occurs within the white fat cells in comparison with brown fat cells.6 The lipolysis process is catalysed by at least three adipocyte-specific enzymes. A monoglyceride lipase catalyses the breakdown of monoglycerides to glycerol and FAs. Hormone-sensitive lipase (HSL) catalyses the hydrolysis of triglycerides to diglycerides and of diglycerides to monoglycerides.7 An adipocyte-specific triglyceride lipase was discovered recently.8 The main role of this enzyme seems to be to catalyse the step of triglyceride to diglyceride. HSL is the most important of the lipases because this is the only enzyme that is subject to hormonal regulation.7

REGULATION OF LIPOLYSIS The lipolytic process is under intense regulation and there is a marked diurnal variability in circulating levels of FAs and glycerol, reflecting hormonal and other regulatory events.1,8–12 The most important regulatory factors are summarized in Table 1. In rodents, a number of hormones have a strong influence on lipolysis. In humans, only catecholamines, natriuretic peptides and insulin have pronounced acute effects. In humans, growth hormone has some long-term permissive effects on lipolysis; in rodents, growth hormone also has pronounced acute effects. Autocrine regulation of lipolysis is also induced by substances produced by the fat cells and/or the stroma vascular cells within the adipose tissue; prostaglandins, adenosine and cytokines, particularly tumour necrosis factor alpha (TNFa). Gender, age, physical activity, nutrition, adipose region and genetic variance are also important factors for lipolysis regulation. The major regulatory pathways for lipolysis in human fat cells are depicted in Figure 1. Catecholamines Catecholamines (noradrenaline and adrenaline) influence lipolysis after they have bound to different adrenoceptor subtypes on the cell-surface membrane of fat cells.7,9,10 These receptors are linked to G-proteins. G-protein receptor complexes regulate adenylate cyclase in the cell membrane. In humans, unlike most other

Table 1. Important regulators of fat cell lipolysis. Hormones Paracrine factors Age Gender Nutrition Physical activity Adipose region Genetic variance

Mainly insulin, catecholamines and natriuretic peptides in humans Cytokines, adenosine and prostaglandins

Mainly subcutaneous versus visceral in humans

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species, at least four adrenoceptors are active. All three b-adrenoceptors are functional in human fat cells but b1 and b2 are most active, whereas b3 is the most active beta-adrenergic receptor in rodents. In addition, humans have functional a2Aadrenoceptors that inhibit lipolysis. The b-receptors couple to Gs-proteins that activate adenylate cyclase so that the production of cyclic AMP increases; this, in turn, activates the protein kinase A complex leading to phosphorylation of HSL and thereby increased hydrolysis of triglycerides. a2A-adrenergic receptors are coupled to Gi-proteins so that adenylate cyclase is inactivated. The latter leads to opposite effects on lipolysis as those described for b-receptors. Thus, in humans, the balance between b- and a-adrenoceptor-mediated catecholamine signal transduction determines the net effect of the hormones on lipolysis. The b effect usually predominates, but there are situations (nutritional and hormonal) when the a effect increases. Natriuretic peptides It was previously thought that catecholamines were the only potent lipolytic hormones in humans. This is different from rodents, where a number of hormones have pronounced and acute stimulatory effects on lipolysis. Recently, it was discovered that natriuretic peptides are markedly lipolytic.11 These effects are observed both in vivo and in situ but only in humans. The lipolytic action of natriuretic peptides is mediated by natriuretic peptide receptor A, which activates guanylyl cyclase so that cyclic GMP is produced. This activates cyclic GMP-dependent protein kinase so that HSL is phosphorylated. The physiological and pathophysiological role of this peptide regulation remains to be established. It has been speculated, however, that natriuretic peptides are involved in the enhanced adipose tissue lipolysis in cachexia because the circulating level of the peptides are often increased in this condition. Insulin Insulin is a powerful inhibitor of lipolysis.12 The hormone binds to specific cell-surface receptors on fat cells causing tyrosine phosphorylation and thereby activation of the insulin receptors. This leads to interactions with signal proteins termed ‘insulin-like receptor substrates’ (IRS-1 and IRS-2). Humans, unlike other species, have no IRS-3.13 IRS-1 and 2, in turn, activate the phosphadityl inositol 3-kinase complex leading to phosphorylation and thereby activation of the enzyme phosphodiesterase 3 A. This enzyme catalyses the breakdown of cyclic AMP to inactive 5 0 AMP so that the intracellular level of cyclic AMP is decreased, which means that protein kinase A and thereby HSL are less activated.14 Paracrine/autocrine regulation It has been known for some time that adipose tissue produces prostaglandins and adenosine. These molecules are powerful inhibitors of lipolysis.15,16 There are specific prostaglandin receptors (E-type) and adenosine receptors in fat cells that are linked to Gi-proteins and inhibit lipolysis in the same fashion as a2A-adrenoceptors. However, the role of adenosine and prostaglandins in lipolysis regulation is probably minor. Cytokines (particularly TNFa) seem, however, to be very important regulators of the spontaneous (basal) lipolytic activity.17,18 TNFa is produced in large amounts by fat cells and other cells within adipose tissue. In humans, unlike

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rodents, it is not released from the adipose tissue into the circulation but acts predominantly as a local factor. Again, important species differences are at hand when TNFa action is concerned. In human fat cells, TNFa stimulates MAP kinases (p44/42 and JNK) through TNFa receptor-1, leading to phosphorylation and decreased production of an adipocyte-specific protein termed ‘perilipin’. This protein coats the adipose lipid droplet and protects it from being hydrolysed by HSL.19 When perilipin is phophorylated or the amount is decreased, its protective ability against HSL action decreases. In rodents, TNFa can also increase the intracellular level of cyclic AMP by inhibiting Gi-protein signalling. Age Age has important effects on lipolysis that are mainly related to the action of catecholamines and insulin.20–22 During the first years of human life, catecholamines have no or little effect on fat cell lipolysis due to prominent a2A-adrenoceptor effects. In this age period, thyroid-stimulating hormone seems to be the most important lipolytic regulator. In elderly subjects, there is also a decrease in catecholamine-induced lipolysis that is mainly due to impaired function of the protein kinase A-HSL complex. The antilipolytic effect of insulin decreases with aging, which, at least in part, can be ascribed to loss of cell-surface insulin receptors. Gender The circulating level of FAs is higher in women than men with equal body mass indices.23 This may be due to larger subcutaneous fat cells and greater fat mass in females than males, causing elevated rates of lipolysis per total body in women. There are also regional variations in catecholamine-stimulated and insulin-inhibited lipolysis that differ between men and women. This gender aspect is probably most important in obesity, as discussed below. Nutritional factors Caloric deprivation such as fasting, starvation or semi-starvation is accompanied by increased mobilization of FAs from fat cells, which is likely to be a major factor behind the loss of fat mass in these situations. The mechanisms behind increased lipolysis during caloric deficit are somewhat uncertain.24 However, there is an increase in basal lipolysis and enhanced lipolytic sensitivity to catecholamines. Physical activity During prolonged exercise, the level of circulating FAs rises due to increased production of catecholamines and decreased production of insulin.25 However, shortand long-term endurance training can also alter lipolysis regulation, making fat cells more sensitive to catecholamine stimulation than in the sedentary state.26 The mechanisms are less well known but seem to involve multiple changes in adrenoceptor signal transduction.

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Heterogenecity of lipolysis Adipose tissue is a heterogeneous organ with regards to lipolysis regulation.27–29 It is well known that the distribution of fat varies within the body. Most adipose tissue (about 80%) is localized in the subcutaneous area, but there are also important fat depots intra-abdominally and perirenally. Visceral adipose tissue is drained by the portal vein to the liver. Other fat depots are drained by the peripheral vein system. There are marked differences in lipolysis between the intra-abdominal (visceral) and subcutaneous adipose tissue depots. The lipolytic effect of catecholamines is more pronounced in visceral than subcutaneous adipose tissue, which, at least in part, is due to depot differences in the signal transduction of b- and a2A-adrenoceptors. Interestingly, these differences are of a primary nature because they are maintained in pre-adipocytes from the two depots when investigated after in vitro differentiation of human pre-adipocytes to fat cells.30 Pre-adipocytes are precursor cells to adipocytes and do not have lipolytic properties until they are converted (i.e. differentiated) to fat cells.31 The antilipolytic effect of insulin is much more pronounced in the subcutaneous than the visceral area, which can be ascribed to lower insulin receptor affinity and less IRS-1 (and therefore less activation) in visceral compared with subcutaneous fat cells. In addition, there are regional differences in paracrine regulation. Adenosine and prostaglandins have stronger antilipolytic properties in subcutaneous compared with visceral fat cells. However, the basal (spontaneous) lipolytic activity is higher in the subcutaneous than the visceral compartment. The regional differences described above are not observed in rodents. If anything, lipolysis is more vivid in subcutaneous than visceral fat of rodents. On the other hand, the depot differences are prominent in humans and are also found in higher primates such as dogs and monkeys. At present, we do not know why hormone-induced release of FAs is more pronounced in the visceral area but spontaneous (basal) release is more pronounced in the subcutaneous area. It is possible that regional lipolysis has a physiological meaning. Since most adipose tissue is subcutaneous, it may be necessary to secure a high FA release in basal (steady-state) conditions. However, the liver may have a particular role in handling FAs in non-steady-state situations, such as during exercise or after meal ingestion, when the levels of catecholamine and insulin, respectively, are high. Since only visceral adipose tissue has direct access to the liver through the portal system, it may be necessary to secure high FA delivery to the liver during non-steady-state situations. Genetic influence Several genetic factors seem to influence adipocyte lipolysis regulation.32 A number of structural variations in genes regulating lipolysis are described that are associated with altered adipocyte lipolytic function (Table 2). Interestingly, these polymorphisms are also associated with obesity. Genetic variance in b2- and b3-adrenergic receptors has functional effects on lipolysis. Furthermore, there is a specific G-coupling protein (Gb3) that links a- as well as b-adrenoceptors to adenylate cyclase. Polymorphism in the G-b3 gene influences catecholamine-induced lipolysis in human fat cells by altering the coupling of b- and a2A-adrenergic receptors to G-proteins. Finally, intronic structural variations in the HSL gene are strongly associated with a decreased effect of catecholamines on lipolysis.

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Table 2. Genetic variance and human adipocyte lipolysis. Gene

Variation

Effect on lipolysis

Associations with obesity

b2-adrenergic receptor

Several variations in amino acids and promoter leading to variable variations in b2-receptor expression and signal transduction Amino acid changes decreasing receptor signal transduction

Increased or decreased lipolytic function of the receptor dependent on type of genetic variance

Yes

Yes

Variations in intronic dinucleotide repeats

Decreased lipolytic function of the receptor Improved lipolytic function of b-adrenergic receptors and enhanced antilipolytic function of a2A-adrenoceptors Decreased lipolytic function of hormone-sensitive lipase

Non-coding variations with unknown function

Decreased b3-adrenergic receptor function

b3-adrenergic receptor G-b3

Hormonesensitive lipase Calpain 10

Yes

Yes

Not known

PATHOPHYSIOLOGICAL STATES A number of pathophysiological conditions are associated with alterations in the regulation of adipocyte lipolysis. The most important are obesity, metabolic (insulin resistance) syndrome, familial combined hyperlipidaemia and polycystic ovarian syndrome (PCOS). However, detailed information is only available for obesity and PCOS, and these conditions will be discussed in more detail below. Obesity Obesity is the most thoroughly investigated pathophysiological state with regards to adipocyte lipolysis.33 The circulating level of FAs is invariably increased in the obese state, indicative of marked alterations in lipolysis. The most consistent finding with regards to lipolysis is enhanced basal lipolytic activity, which has been observed in all adipose regions examined. Several factors contribute to this increase, but fat cell size and TNFa are probably the most important for the increased basal rate of lipolysis in obesity; this increase in lipolysis results in elevated circulating levels of FAs. There is a very strong correlation between the rate of basal lipolysis and the size of fat cells.34 The molecular mechanism behind this relationship is not known but could, at least in part, be due to the fact that large fat cells contain more cyclic AMP than small ones. With regards to TNFa, there is a marked increase in the production of this cytokine by adipose tissue in obesity. Thus, increased TNFa production will stimulate the MAP kinases in adipocytes, thus altering the action of perilipin and leading to an enhanced basal rate of lipolysis. Circulating levels of FAs normalize after weight reduction of the obese, probably, at least in part, due to a decrease in fat cell size and a decrease in adipose TNFa production. With regards to the antilipolytic effect of insulin, it is less clear whether this action is altered in the obese state.33,34 It is difficult to study insulin-induced antilipolysis because

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it is strongly influenced by the prevailing catecholamine concentration (catecholamines counteract the antilipolytic effect of insulin). Consequently, normal decreased and increased antilipolytic effects of insulin have been observed among the obese. However, insulin receptor transduction is decreased, mainly due to low IRS-1 content in the obese fat cells, and the resistance of insulin action on glucose metabolism in fat cells is readily demonstrated in human obesity. Thus, impaired insulin signal transduction of fat cells is indeed present in the obese state. Finally, the action of insulin on visceral fat depots has, to the best of the author’s knowledge, not been investigated in obesity. It is, thus, likely that insulin action on lipolysis is less impaired than that of glucose metabolism in adipocytes of the obese, and the level of resistance is dependent on other concomitant factors such as physical activity, stress levels, food intake and the adipose region examined. Therefore, the effect of insulin on adipocyte lipolysis may vary between normal and impaired in the obese. It is well established that catecholamine action is markedly altered in adipose tissue of the obese.33 However, important regional variations exist.27–29 In subcutaneous adipose tissue, the lipolytic effect of catecholamines is decreased. At least three mechanisms have been linked to this resistance: increased function of a2Aadrenoceptors, decreased expression of b2-adrenoceptors and decreased expression of HSL. Lipolytic resistance is more readily observed in obese men than obese women. With regards to visceral adipose tissue, the opposite is true compared with subcutaneous fat tissue. Catecholamine-induced lipolysis is markedly increased in visceral fat cells, which is due to increased function of the b3-adrenoceptors and decreased function of the a2A-adrenoceptors. The impact of obesity on catecholamine effects in visceral fat cells is more readily observed among men than women. It is quite possible that lipolysis is a key factor in the adverse metabolic consequences observed in subjects with so-called ‘abdominal obesity’, particularly when there is visceral fat accumulation.35,36 When the regional aspects of catecholamine-induced lipolysis and insulin inhibition of lipolysis are taken into consideration, there is a redistribution of FA mobilization during situations of catecholamine excess, such as mental stress and physical activity, and during insulin excess, such as following food intake. Fewer FAs are produced from the subcutaneous fat depot due to local catecholamine resistance and high insulin sensitivity of antilipolysis, but more FAs are produced from the visceral fat depot due to local catecholamine super-sensitivity and insulin resistance of lipolysis in this depot. This will favour portal release of FAs and could be an important factor behind the more readily observed metabolic abnormalities among obese subjects who accumulate fat centrally compared with those who deposit fat peripherally. Abnormal regional lipolysis could also be a factor behind the gender differences in obesity-associated metabolic complications, because regional variations in lipolysis are more marked in obese men than obese women. This theory is mainly based on studies of fat cells in vitro. However, the in vitro results were recently confirmed in vitro. It was demonstrated that splanchnic (i.e. visceral) lipolysis was increased in obesity and more markedly so in males than females.37 It is likely that the genetic variation discussed above also contributes to the alterations in catecholamine action in obesity. Genetic variance in HSL, b-adrenoceptors and G-b3 may cause a decreased lipolytic effect of catecholamines in subcutaneous adipose tissue that will promote net fat storage in this compartment. Furthermore, non-obese subjects with heredity for obesity among first-degree relatives have lipolytic resistance to catecholamines in their subcutaneous fat cells.32 It is tempting to speculate that the links between structural gene variation, altered lipolysis and obesity are of pathophysiological importance.

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PCOS PCOS has many similarities to the metabolic (insulin resistance) syndrome.38 PCOS is a hyperandrogenic state that is associated with a male type of fat distribution. Many PCOS women are prone to upper body obesity and have an increased risk of developing type 2 diabetes mellitus. Lipolysis regulation has been investigated somewhat intensely in PCOS.39 Since most of these studies have been performed on relatively young and non-obese women, it is possible to separate alterations in lipolysis that are primarily related to PCOS from those that are secondary to the obesity. The basal rate of lipolysis in PCOS is normal both in subcutaneous and visceral adipose tissue. However, the fat cell size is slightly increased among PCOS women, at least in subcutaneous adipose tissue, in spite of normal total body fat content. The antilipolytic effect of insulin is decreased in subcutaneous fat cells but is quite normal in the visceral fat depot. The possible alterations of insulin receptor signal transduction in PCOS remain to be established.40 With regards to catecholamines, regional adipose effects are observed that are similar to those in obesity. Thus, catecholamine action is decreased in subcutaneous fat cells, which is linked to decreased expression of b2adrenoceptors and HSL. In visceral fat cells, the lipolytic effect of catecholamines is increased, and this has been attributed to alterations in the stoichometric proportions of several of the components in the protein kinase A-HSL complex. It appears that abnormal lipolysis in subcutaneous adipose tissue of PCOS women can be explained, at least in part, by testosterone. PCOS is a classic hyperandrogenic state. In vitro exposure of subcutaneous fat cells but not visceral fat cells to testosterone or dihydrotestosterone induces catecholamine resistance of lipolysis that can be attributed to low expression of HSL and b2-adrenoceptors. This is contrary to findings in rodent fat cells, where testosterone increases the lipolytic effect of catecholamines. When all lipolysis data are considered together in PCOS, it appears that the major change in this condition concerns the action of catecholamines, leading to hormone resistance in the subcutaneous fat depot and increased action in the visceral fat depot. Similar to the changes in obesity, this will lead to a redistribution of FA mobilization in stressful situations favouring visceral fat. This might explain some of the metabolic abnormalities seen in women with PCOS. Other pathophysiological states Lipolysis has been investigated in subcutaneous adipose tissue of subjects with the metabolic (insulin resistance) syndrome and in familial combined hyperlipidaemia.41,42 In both conditions, there is impaired lipolytic function of catecholamines which, above all, is caused by decreased expression/function of HSL. To the author’s knowledge, no studies have been published regarding the visceral fat depot or the antilipolytic effect of insulin in these conditions.

CONCLUSIONS Fat cell lipolysis is subject to intense regulation by hormones, cytokines, physiological factors and pathophysiological factors. Furthermore, genetic variation is of importance. Major species differences in the regulation of fat cell lipolysis exist, making it difficult to draw clinical conclusions from animal experiments. A number of

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conditions that are associated with insulin resistance, such as obesity, metabolic syndrome, PCOS and familial combined hyperlipidaemia, also display alterations in fat cell lipolysis. It is less clear how much insulin resistance per se contributes to altered lipolysis in the above-mentioned conditions. However, altered catecholamine action on lipolysis is well documented in obesity and PCOS. In these two conditions, the lipolytic effect of catecholamine action is decreased in the subcutaneous adipose tissue but increased in visceral fat tissue. This leads to a redistribution of FA mobilization in stressful situations, exposing the liver to high amounts of FAs, which is likely to be an important pathophysiological factor behind many of the metabolic abnormalities that are observed in obesity and PCOS. The redistribution of lipolysis could also, in part, explain the gender effect on obesity-associated metabolic complications since the regional catecholamine abnormalities in obesity are most pronounced in men and influenced by testosterone. In obesity, there is also a marked increase in the basal (spontaneous) lipolytic activity in all adipose regions which is caused, at least in part, by enlarged fat cell size and increased lipolysis by TNFa. The change in basal lipolysis and the increased fat mass per se could be the major causes behind elevated FA levels in the peripheral circulation in the obese state. In the future, it may be possible to gain new and perhaps better treatment programmes of insulin resistance targeting fat cell lipolysis. Some FA-lowering compounds are already available. Nicotinic acid analogues act on specific antilipolytic fat cell receptors43, and glitazones act on peroxisome proliferative receptor gamma which regulates adipocyte FA metabolism.44 Practice points † catecholamines and insulin are the most important hormones regulating human fat cell lipolysis † there are regional variations in lipolysis † lipolytic activity in the resting state is higher in subcutaneous fat cells than in visceral fat cells † during hormone stimulation (catecholamines, insulin), lipolytic activity is higher in visceral fat cells than in subcutaneous fat cells † there is marked dysregulation of adipocyte lipolysis in obesity and PCOS † in both conditions, the lipolytic effect of catecholamines is increased in visceral fat cells but decreased in subcutaneous fat cells † this favours release of FAs to the liver, which is directly linked to visceral adipose tissue by the portal vein † high portal FA release disturbs liver function, resulting in dyslipidaemia, hyperinsulinaemia and glucose intolerance

Research agenda † circulating FAs are elevated in most obese subjects after an overnight fast † this might be due to increased action on lipolysis by TNFa which is produced by adipose tissue in increased amounts among the obese † the enlarged fat cell size per se might also contribute to increased FA levels in the obese

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