Obesity

Obesity (body mass index (BMI) >30 kg/m2) represents the most common complex metabolic disorder in the industrialized world and its prevalence continues to grow. Insulin resistance is closely related to obesity, and predisposes fat subjects to certain complications, including hypertension, hyperlipidemia, cardiovascular diseases and Type 2 diabetes (Reaven 1988). There is a close correlation between degree of obesity and insulin resistance in diabetics and non-diabetics. Risk of Type 2 diabetes is 11 times greater with a BMI increase from 20 to 30 kg/m2 (Carey et al., 1997).

Since obesity represents an expansion of the fatty tissue mass, insulin resistance related to excess weight could be explained by the production by fatty tissue of factors whose systemic action renders some subjects more resistant to insulin than others. The cytokines TNFa, IL-6 and IL-1 play a major regulatory role in metabolizing fatty tissue. Their increased synthesis following an inflammatory response constitutes a basic element in obesity and related metabolic disorders.

One of the many secretions from adipocytes, TNFa plays an important role in glucose and lipid metabolism. TNFa is considered an adipostat, which protects fatty cells against lipid overload (Kern et al., 1995). TNFa produced locally by fatty tissue could regulate the size of adipocytes. An overproduction in obese subjects could limit the size of adipocytes through a combination of several catabolic channels. Increased production of TNFa is proportional to fat mass (BMI) and hyperinsulinemia (Bullo et al., 2002). This cytokine is implicated as a causal factor in adiposity associated with insulin resistance and in the pathogenesis of Type 2 diabetes. The metabolic effects of TNFa would be due to several mechanisms including (Hotamisligil, 2000; Moller, 2000):

Reduced function of genes required to maintain insulin’s normal activity (Hotamisligil et al., 1995; 1993; Kern et al., 1995).
Indirect action by stimulating the production of stress hormones (Grimble, 2002)
Direct action on the insulin signaling pathway. Reduction in insulin receptor tyrosine phosphorylation in muscle and fat tissue by stimulation of the TNF p55 receptor (TNFR) and of sphingomyelinase is observed in Type 2 diabetes (Hotamisligil, 1999; Kanety et al., 1995). At the molecular level, TNFa causes phosphorylation in the serine substrate of the IRS-1 insulin receptor by induction of SOCS-3. This modified form of IRS-1 has an inhibitory action (Hotamisligil et al., 1996). TNFa also interferes with transport by decreasing synthesis of GLUT-4 carriers (Halle et al., 1998; Stephens 1998; et al., 1997). These effects involve the production of H2O2 (Hansen et al., 1999). Oxidative stress due to increased production of TNFa would also occur, inducing insulin resistance at an early stage of the disease. In addition, oxidative stress would play a major role in the development of complications related to diabetes (Wierusz-Wysocka et al., 1995).
Inhibition of lipoprotein lipase (LPL) and stimulation of hepatic lipolysis with elevated levels of free fatty acids (Patton et al., 1986).
Nutritional effects, including de-differentiation involving negative regulation of ‘peroxisome proliferator activated receptor g’ (PPAR-g), an important receptor for insulin sensitivity and regulating cell volume and induction of apoptosis (Coppack, 2001). PPAR-g activity is also modulated by insulin, leptin, lipids and growth factors (Mueller-Wieland et al., 2001). Reduction in the activity of transcription factors such as PPAR would play an important role in the pathogenesis of cardiovascular diseases. The PPARs modulate the recruitment of white blood cells at the endothelial level, control the inflammatory reaction and lipid homeostasis of monocytes/macrophages, and regulate the production of inflammatory cytokines by smooth muscle cells. Clinical studies have shown the anti-atherosclerotic activity of PPAR-a and PPAR-g in vivo ((Duval et al., 2002).
Increase in type 1 inhibitors of plasminogen activator in adipocytes (PAI-1). The increased incidence of cardiovascular diseases in obese subjects is related to elevated plasma levels of hemostatic factors such as fibrinogen, factor VII and inhibitor I of PAI-1. Exaggerated PAI-1 concentrations interfere with fibrin clearance and thereby facilitate formation of thromboses, including myocardial infarctions (Samad et al., 1999).
TNFa induces elevated plasma levels of insulin and increases the expression of TGFb in fatty tissue. Insulin and TGFb increase PAI-1 activity in plasma and in fatty tissue (Samad et al., 1998). TGFb exhibits extensive biological activity and can be implicated in atherosclerosis (Wang et al.,1997) and renal fibrosis (Border, 1994), two common complications of obesity.
TNFa exhibits cytotoxic activity for vascular endothelium and cartilage, bone and muscle tissue (Cavaillon 1995).

Other factors besides TNF are involved in insulin resistance and interfere with lipid metabolism:

IL-6

IL-6 is secreted by adipocytes. The synthesis of this cytokine is increased in obese subjects. IL-6 is involved in insulin resistance (Kern et al., 2001). Like TNFa, IL-6 inhibits the expression of lipoprotein lipase (Crichton et al., 1996) but, unlike TNFa, does not stimulate lypolysis (Feingold et al., 1992).

Angiotensin II

Angiotensin II interferes with the intracellular signalling cascade for insulin analogousto that of TNFa by stimulating tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2, which leads to binding of IRS to phosphatidylinositol 3-kinase (PI3K) (Folli et al., 1999). Angiotensin II may contribute to insulin resistance in hypertensive subjects exhibiting increased activity in the renin-angiotensin system. TNFa may indirectly play a role in hypertension since this cytokine stimulates the expression of angiotensin in the liver ((Brasier et al., 1996).

Leptin

Adipocytes secrete leptin, which is a hormone with a secondary cytokine structure that exercises pro-inflammatory activity, and whose concentrations are related to body fat. Leptin receptors are transmembrane proteins similar to the IL-6 receptors (Girard, 1997). Leptin constitutes a key element in long-term regulation of food intake and homeostasis of body weight. Leptin acts at the level of the central nervous system through a specific receptor and the mediation of various neuropeptides. A leptin receptor at the level of the choroid plexus is responsible for passage across the hematomeningeal (blood-brain) barrier. Interaction of leptin with the hypothalamic receptor reduces the production of orexigenic neuromediators (i.e., which stimulate food ingestion) such as NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexines and AGRP (Agouti-related peptide), and increases the expression of anorexigenic neuropeptides, including aMSH (a melanocyte stimulating hormone), which acts on MC4R (Melanocortin-4 receptor) and CART (cocaine and amphetamine-regulated transcript) and CRH (corticotropin releasing hormone) (Jequier, 2002). Elevated levels of leptin reduce the feeling of hunger, reduce body weight, increase the body’s energy output, increase activity of the sympathetic nervous system as regards the kidneys, adrenal glands and fatty tissue and thalamic thermogenesis. Leptin also has specific effects on the gastrointestinal system (Attele et al., 2002), which suggests that food intake and homeostasis are regulated by central and peripheral signals. Leptin also has multiple effects on the endocrine, cardiovascular and autonomic nervous systems and the kidneys (Haynes et al., 1998). Like TNFa, leptin is involved in insulin resistance, but the mechanism of this interaction is still unknown.

TNFa is involved in insulin resistance in muscle and fat tissues. Obese Sprague-Dawley (S-D) rats that quickly develop insulin resistance by reducing muscular transport of glucose show increased muscle concentrations of TNFa. Administration of anti-TNFa IgG to S-D rats reduces insulin resistance and causes a reduction in the muscle levels of TNFa (Borst and Bagby, 2002). The same effect was observed in the fatty tissue of fa/fa obese rats (Hotamisligil et al., 1993). In humans, elevated tissue levels of TNFa in adipocytes and muscles together with an increased release into the (blood) circulation were observed in obese cases (Hotamisligil et al., 1995; Kern et al., 1995; Nilsson et al., 1998). These TNFa plasma levels are relatively weak and the question whether this circulating TNFa exerts a systemic biological action or effect on other organs currently remains unknown. TNFa may bond to a soluble receptor that inhibits its biological activity (Engelberts et al., 1991); the systemic effects of TNFa produced by adipose and muscle tissue would therefore be limited. However, the small amount of circulating TNFa observed in insulin resistant subjects could reflect an inflammatory source (Nilsson et al., 1998), and plasma levels may also increase in the advanced stages of disease, following other metabolic changes (Zinman et al., 1999).

Despite elevated leptin concentrations in proportion to body fat in obese subjects, the expected responses (reduction of feeling of hunger and increase in energy expended) have not been observed. These subjects are resistant to endogenous leptin. This resistance is also highlighted by the absence of leptin effect on excess weight by the administration of leptin during the therapeutic trials. The many mechanisms that play a role in leptin resistance act both centrally and peripherally, and include:

Reduction of leptin transport across the blood-brain barrier
Inhibition of the leptin signalling pathways of hypothalamic neurons (Jecquier, 2002).
Expression and increased secretion of the receptor antagonist for IL-1 (IL-1Ra) related to obesity. IL-1Ra opposes the action of leptin at the hypothalamic level (Meier et al., 2002).
The increased expression of protein-tyrosine phosphatase 1B (PTP1B) which exerts a negative regulation on leptin signalling pathways (Cheng et al., 2002). The PTPs are necessary for dephosphorylation of the insulin receptor and its initial cellular substrates. The exaggerated expression of PTP1B, with its altered catalytic activity in obese subjects, also plays a part in insulin resistance (Cheung et al., 1999).

The expression of leptin may also be partially inhibited in obese subjects by:

catecholamines via beta-adrenergic receptors and cAMP
long-chain fatty acids via PPAR (Girard, 1997)
TNFa and IL-1b (Bruun et al., 2002)

Fatty acids

Free fatty acids generate peripheral insulin resistance proportional to their serum level (Boden et al., 1994) with an accumulation of lipids in the muscle tissue. This interaction may be due to the accumulation of long-chain acyl CoA that changes the action of insulin by a chronic burst of isoforms of protein kinase C(Kraegen et al., 2001).

Prolonged elevation of free fatty acid levels also induces a deficit of B-cells (lipotoxicity) similar to that observed in Type 2 diabetes (Mason et al., 1999), which would be due to apoptosis via de novo formation of ceramides and an increased production of nitric oxide (Shimabukuro et al., 1998).

Food intolerance and obesity

Chronic inflammation via action of TNFa, IL-6, leptin, angiotensin II generates insulin resistance and lipid metabolism disorders predisposing to complications associated with excess weight. In fact, most obese subjects have elevated levels of inflammatory markers that correlate closely with the degree of obesity and with the degree of insulin resistance (Invitti, 2002). This phenomenon is also observed in obese children free of any other pathology. The various mediators involved in metabolic disorders related to obesity stimulate each other, creating a vicious circle. It is thus essential to thwart chronic activation of the immune system to re-establish normal metabolic activity.
Since a major part of chronic inflammation is dietary in origin, an exclusion diet based on dietary IgG antiantigen antibody titres makes it possible to cut short the vicious circle of effects of chronic and repeated activation of the immune system.

Guidelines for measuring food-related IgG antiantigens

In obese subjects: Prevention of complications related to obesity (insulin resistance, high blood pressure and cardiovascular diseases). Since the chronic inflammatory response causes an accumulation of lipids in adipose and muscle tissue, avoidance of foods in question would make weight loss possible without necessarily resorting to a hypocaloric diet. At least part of the excess weight is related to a disrupted energy balance following an inadequate immune response.
Preliminary results after a three-month follow-up in patients showed that following a diet based on the profile of food intolerance is very encouraging, since more then 90% of individuals recorded an average weight loss of 8 kg.