Elsevier

Nutrition

Volume 21, Issue 6, June 2005, Pages 762-773
Nutrition

Review
Pathophysiology of metabolic syndrome X and its links to the perinatal period

https://doi.org/10.1016/j.nut.2004.11.005Get rights and content

Abstract

It is proposed that metabolic syndrome X is initiated in the perinatal period as a low-grade systemic inflammatory condition. Increased consumption of energy-dense diets by pregnant women and lactating mothers suppresses the activities of Δ-6 and Δ-5 desaturases not only in maternal tissues but also in fetal liver and the placenta, resulting in decreased plasma and tissue concentrations of long-chain polyunsaturated fatty acids ω-6 arachidonic acid (AA), ω-3 eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). EPA, DHA, and AA have negative feedback control on tumor necrosis factor-α and IL-6 synthesis. Hence, EPA, DHA, and AA deficiencies induced by an energy-dense diet increase generation of tumor necrosis factor-α and interleukin-6, markers of inflammation that in turn decrease production of endothelial nitric oxide and adiponectin to induce insulin resistance in maternal and fetal tissues. Increased concentrations of tumor necrosis factor-α and interleukin-6 enhance expression and activity of 11β-hydroxysteroid dehydrogenase type 1 enzyme, which produces abdominal obesity, insulin resistance, hyperlipidemia, hyperphagia, and hyperleptinemia, characteristic features of metabolic syndrome X. Continued consumption of an energy-dense diet in childhood aggravates these molecular events. This implies that supplementation of long-chain polyunsaturated fatty acids (especially AA, EPA, and DHA in appropriate ratios) from the perinatal period through adulthood could prevent, arrest, or postpone development of metabolic syndrome X.

Introduction

Metabolic syndrome X is characterized by abdominal obesity, atherosclerosis, insulin resistance and hyperinsulinemia, hyperlipidemias, essential hypertension, type 2 diabetes mellitus, and coronary heart disease (CHD). Other features of metabolic syndrome X are hyperfibrinogenemia, increased plasminogen activator inhibitor-1, decreased tissue plasminogen activator, nephropathy, microalbuminuria, and hyperuricemia. Although the incidence of metabolic syndrome X is assuming epidemic proportions in almost all countries around the globe, the cause for this increasing incidence is not clear. Genetics of various populations have not changes in the past 100 y, so a dominant role for environmental factors in the increasing incidence of metabolic syndrome X is suspected. Identification of causes and/or etiologic factors for the development of metabolic syndrome X is important so that suitable measures can be instituted to prevent and cure the syndrome.

Section snippets

Incidence of metabolic syndrome X

By the year 2010, in the United States alone there may be about 50 to 75 million or more people who have metabolic syndrome X. It is more common on the Indian subcontinent and has been attributed to genetic factors. One common feature of metabolic syndrome X is the presence of insulin resistance and consequent hyperinsulinemia. Many subjects with abdominal obesity, hypertension, type 2 diabetes, hyperlipidemias, CHD, and stroke show insulin resistance and impaired glucose tolerance (IGT). It is

Different depots of fat display wide differences in their biochemical properties

Adipose tissue distribution is an important predictor of obesity-associated morbidity and mortality. Abdominal obesity is common in subjects with metabolic syndrome X and is a risk factor for CHD. Adipose tissue distribution is dependent on genetic, environmental, and hormonal factors. There are distinct differences in the distribution of adipose tissue in males and females, and adipose tissue in different regions of the body is functionally different. Females have more subcutaneous and

11β-Hydroxysteroid dehydrogenase type 1 and abdominal obesity

Mice that overexpress the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme selectively in adipose tissue develop abdominal obesity and exhibit insulin resistance, type 2 diabetes, hyperlipidemia, hyperphagia, and hyperleptinemia [6], [7], features that are similar to those seen in subjects with metabolic syndrome X. This indicates that abdominal obesity is akin to localized Cushing’s syndrome. Increased activity of 11β-HSD-1 in the abdominal adipose tissue compared with subcutaneous

Metabolic syndrome X as a low-grade systemic inflammatory condition: obesity, insulin resistance, and type 2 diabetes mellitus

There is evidence to suggest that low-grade systemic inflammation occurs in metabolic syndrome X [8], [9], [10]. Plasma levels of C-reactive protein (CRP), TNF-α, and IL-6, markers of inflammation, are higher in subjects who have obesity, insulin resistance, essential hypertension, type 2 diabetes, and CHD [8], [9], [10], [11], [12], [13], [14], [15], [16]. A direct positive correlation exists between body mass index and CRP in otherwise healthy children and adults. Higher plasma concentrations

Free radicals, nitric oxide, and metabolic syndrome X

Superoxide anion interacts with nitric oxide (NO) and inactivates it, thus producing peroxynitrite radical, which has cytotoxic actions. Increased superoxide production accounts for a significant proportion of the NO deficit seen in diabetes, hypertension, and consequent vascular dysfunction [26], [27]. Decreased endothelial NO (eNO) and increased free radical generation (especially superoxide anion) is seen not only in diabetes and hypertension but also in insulin resistance, obesity, and CHD

Adiponectin and metabolic syndrome X

Adiponectin is a 29-kDa adipocyte protein that is secreted by adipose cells. Plasma adiponectin levels are decreased in subjects with obesity and type 2 diabetes mellitus. An inverse association exists between plasma adiponectin levels and insulin resistance, with lower concentrations of adiponectin indicating greater resistance to the actions of insulin [35]. Women have higher plasma adiponectin levels than do men despite the fact that women have larger amounts of adipose tissue. A significant

Essential hypertension is an inflammatory condition

High circulating IL-6 levels in women with hypertension and insulin resistance in men has been described [46]. A significant graded relation between blood pressure and levels of intercellular adhesion molecule-1 and IL-6 was noted [47]. Increased pulse pressure is associated with high CRP levels among healthy U.S. adults [48]. A direct correlation between plasma CRP levels and advancing age, body mass index, systolic blood pressure, HDL, smoking, and hormone replacement therapy was reported in

Metabolic syndrome X is a low-grade systemic inflammatory condition

Increased concentrations of proinflammatory cytokines, CRP, and free radicals and decreased concentrations of eNO, antioxidants, anti-inflammatory cytokines, and adiponectin are common in abdominal obesity, insulin resistance, type 2 diabetes mellitus, hypertension, CHD, and hyperlipidemia [53], [54], [55]. This implies that metabolic syndrome X is an inflammatory condition [8]. TNF-α and IL-6 increase, whereas insulin-like growth factor-I (IGF-I) and insulin, suppress the activity of 11β-HSD-1

Perinatal origins of metabolic syndrome X

Cardiovascular disease and type 2 diabetes may have their origins early in life [7], [8], [9], [58], [67], [68]. Low birth weight leads to a high prevalence of metabolic syndrome X in later life [58], [69]. Babies with low birth weights have 10 times greater chance of developing metabolic syndrome X than do those whose birth weights are normal. However, this relation has been disputed. It was suggested that postnatal nutrition and growth are equally important in the development of metabolic

ω-3 and ω-6 long-chain polyunsaturated fatty acids and metabolic syndrome X

The ω-3 and ω-6 fatty acids are essential for fetal growth and development including that of the brain [73], [74], [75]. Dietary linoleic acid and α-linolenic acid are essential fatty acids that are desaturated and elongated to form their respective long-chain metabolites [76], [77], [78] (Figure 2 illustrates the metabolism of essential fatty acids). Newborn infants, especially preterm infants, have limited capacity to form eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and

Maternal malnutrition, LCPUFAs, and metabolic syndrome X

Malnutrition can be defined as undernutrition and as overnutrition. Maternal protein restriction or increased consumption of saturated and/or trans-fatty acids and energy-rich diets (maternal overnutrition) during pregnancy decrease the activity of Δ-6 and Δ-5 desaturase enzymes that are essential for the conversion of dietary essential fatty acids linoleic acid and α-linolenic acid to their respective LCPUFAs. Hence, maternal malnutrition (undernutrition and overnutrition) leads to maternal

What sequence of events lead to metabolic syndrome X?

I propose that the physiologic response to even normal food intake (containing carbohydrates, proteins, and fats and mixed meals) is an increase in the production of TNF-α and IL-6 and consequent increase in plasma CRP and decreases in anti-inflammatory cytokines IL-4 and IL-10 and in adiponectin. TNF-α and IL-6 induce oxidative stress and activate nuclear factor-κB, which induces insulin resistance and, hence, hyperinsulinemia. Insulin secreted in response to food intake is not only intended

Conclusions and therapeutic implications

It is evident from the preceding discussion that LCPUFAs, cytokines, and 11β-HSD-1 interact with each other and play an important role in the pathobiology of metabolic syndrome X (Figure 3). This suggests that these indices can be used as markers to predict future development of metabolic syndrome X and its prognosis. In addition, these indices may be used to predict the response to the interventions employed in the prevention or postponement of metabolic syndrome X. Thus, I propose the

References (112)

  • V.-P. Valkonen et al.

    Risk of acute coronary events and serum concentrations of asymmetrical dimethylarginine

    Lancet

    (2001)
  • M.D. Savvidou et al.

    Endothelial dysfunction and raised plasma concentrations of asymmetrical dimethylarginine in pregnant women who subsequently develop pre-eclampsia

    Lancet

    (2003)
  • R.S. Lindsay et al.

    Adiponectin and development of type 2 diabetes in the Pima Indian population

    Lancet

    (2002)
  • J. Spranger et al.

    Adiponectin and protection against type 2 diabetes mellitus

    Lancet

    (2003)
  • S. Jovinge et al.

    Evidence for a role of tumor necrosis factor alpha in disturbances of triglycerides and glucose metabolism predisposing to coronary heart disease

    Metabolism

    (1998)
  • U.N. Das

    Nutritional factors in the pathobiology of human essential hypertension

    Nutrition

    (2001)
  • U.N. Das

    Is insulin an anti-inflammatory molecule?

    Nutrition

    (2001)
  • R. Kalhan et al.

    Altered lipid profile, leptin, insulin, and anthropometry in offspring of South Asian immigrants in the United States

    Metabolism

    (2001)
  • U.N. Das

    Pathobiology of metabolic syndrome X in obese and non-obese South Asian Indiansfurther discussion and some suggestions

    Nutrition

    (2003)
  • U.N. Das

    The lipids that matter from infant nutrition to insulin resistance

    Prostaglandins Leukot Essent Fatty Acids

    (2002)
  • A.A. Leaf et al.

    Long chain polyunsaturated fatty acids and fetal growth

    Early Hum Dev

    (1992)
  • U.N. Das

    Essential fatty acids as possible mediators of the actions of statins

    Prostaglandins Leukot Essent Fatty Acids

    (2001)
  • J.E. Reseland et al.

    Reduction of leptin gene expression by dietary polyunsaturated fatty acids

    J Lipid Res

    (2001)
  • U.N. Das

    Beneficial effect(s) of n-3 fatty acids in cardiovascular diseasesbut, why and how?

    Prostaglandins Leukot Essent Fatty Acids

    (2000)
  • U.N. Das

    The brain-lipid-heart connection

    Nutrition

    (2001)
  • Y.-J. Huang et al.

    Amelioration of insulin resistance and hypertension in a fructose-fed rat model with fish oil supplementation

    Metabolism

    (1997)
  • Y. Mori et al.

    Influence of highly purified eicosapentaenoic acid ethyl ester on insulin resistance in the Otsuka Long-Evans Tokushima fatty rat, a model of spontaneous non-insulin dependent diabetes mellitus

    Metabolism

    (1997)
  • U.N. Das

    Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus, and coronary heart disease

    Prostaglandins Leukot Essent Fatty Acids

    (1995)
  • U.N. Das et al.

    Essential fatty acid metabolism in South Indians

    Prostaglandins Leukot Essent Fatty Acids

    (1994)
  • I.J. Bujalska et al.

    Does central obesity reflect “Cushing’s disease of the omentum?”

    Lancet

    (1997)
  • B.C. Hansen et al.

    Changes in insulin responses and binding in adipocytes from monkeys with obesity progressing to diabetes

    Int J Obesity

    (1988)
  • P. Bjortorp

    Adipose tissue distribution and function

    Int J Obesity

    (1991)
  • O. Pederson et al.

    Insulin binding and action on fat cells from young healthy females and males

    Am J Physiol

    (1982)
  • U.N. Das

    Sex differences in the number of adipose cells

    XX vs. XY

    (2003)
  • H. Masuzaki et al.

    A transgenic model of visceral obesity and the metabolic syndrome

    Science

    (2001)
  • U.N. Das

    Is metabolic syndrome X an inflammatory condition?

    Exp Biol Med

    (2002)
  • M.A. Albert et al.

    Plasma concentration of C-reactive protein and the calculated Framingham coronary heart disease risk score

    Circulation

    (2003)
  • I.M. van der Meer et al.

    C-reactive protein predicts progression of atherosclerosis measured as various sites in the arterial tree. The Rotterdam study

    Stroke

    (2002)
  • G. Luc et al.

    C-reactive protein, interleukins-6, and fibrinogen as predictors of coronary heart disease. The PRIME study

    Arterioscler Thromb Vasc Biol

    (2003)
  • P.M. Ridker et al.

    Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

    N Engl J Med

    (1997)
  • G. Engstrom et al.

    Inflammation-sensitive plasma proteins are associated with future weight gain

    Diabetes

    (2003)
  • L. Mosca

    C-reactive protein-to screen or not to screen

    N Engl J Med

    (2002)
  • J.I. Barzilay et al.

    The relation of markers of inflammation to the development of glucose disorders in the elderly

    Diabetes

    (2001)
  • J.P. Kirwan et al.

    Human aging is associated with altered TNF-α production during hyperglycemia and hyperinsulinemia

    Am J Physiol

    (2001)
  • K. Esposito et al.

    Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans. Role of oxidative stress

    Circulation

    (2002)
  • P. Mohanty et al.

    Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes

    J Clin Endocrinol Metab

    (2000)
  • I.K. Mohan et al.

    Oxidant stress, anti-oxidants and nitric oxide in non-insulin dependent diabetes mellitus

    Med Sci Res

    (1997)
  • K.V. Kumar et al.

    Are free radicals involved in the pathobiology of human essential hypertension?

    Free Radic Res Commun

    (1993)
  • U.N. Das

    Oxy radicals and their clinical implications

    Curr Sci

    (1993)
  • K.V. Kumar et al.

    Lipid peroxides and essential fatty acids in patients with coronary heart disease

    J Nutr Med

    (1994)
  • Cited by (36)

    • Mediterranean diet is beneficial: But, how, and why?

      2017, Role of the Mediterranean Diet in the Brain and Neurodegenerative Diseases
    • Circulating visfatin levels in healthy preterm infants are independently associated with high-density lipoprotein cholesterol levels and dietary long-chain polyunsaturated fatty acids

      2011, Metabolism: Clinical and Experimental
      Citation Excerpt :

      Dietary n-3 LCPUFAs have been linked to beneficial effects against insulin resistance and to a favorable impact on lipidemic profile [10]. It is also worth noting that dietary LCPUFAs during the perinatal period may affect neonatal programming and reduce the risk of metabolic syndrome in later life [11,12]. Preterm infants are at risk for the later development of insulin resistance and possibly other components of the metabolic syndrome [13,14].

    • Obesity: Genes, brain, gut, and environment

      2010, Nutrition
      Citation Excerpt :

      Insulin signaling has a role in the regulation of food intake, neuronal growth, and differentiation by regulating neurotransmitter release and synaptic plasticity in the central nervous system. Neuron-specific disruption of the insulin-receptor gene (NIRKO) in mice induces obesity, insulin resistance, hyperinsulinemia, and type 2 diabetes without interfering with brain development [121–123]. This indicates that a decrease in the number of insulin receptors, defects in the function of insulin receptors, and insulin lack or resistance in the brain leads to the development of obesity and type 2 diabetes mellitus even when pancreatic β-cells are normal.

    • Lipid compounds of the umbilical cord artery and their alterations in preeclampsia

      2009, Atherosclerosis
      Citation Excerpt :

      The lipid content and composition in various organs change during development, ageing and pathological processes. The fatty acids serve as a source of energy for a number of cells; many are substrates for synthesis of regulatory molecules: prostaglandins, thromboxanes and leukotrienes [23,24]. Several lipids are constituents of biological membranes, which separate the cells from the surrounding hydrophilic environment and contribute to organelle structures.

    • HPA axis programming by maternal undernutrition in the male rat offspring

      2007, Psychoneuroendocrinology
      Citation Excerpt :

      Because glucocorticoids influence the activity of almost every cell in the body, the dysregulation of the HPA axis activity may participate to the development of several diseases. For example, it has been suggested that an inappropriate feedback in the HPA axis may play a role in the development of metabolic and cognitive disorders (Laugero, 2004; Das, 2005). Glucocorticoid hormones also play a pivotal role in the cross-talk between immune and neuroendocrine systems, and are implicated in both immunomodulation and inflammatory processes.

    View all citing articles on Scopus
    View full text