In this chapter the authors report on their experience with the analysis and modeling of data obtained from studies of animal models related to obesity and metabolic syndrome. The complex interactions of genetic and environmental factors contributing to the failure of energy balance that lead to obesity, as well as tight systemic regulation to maintain energy homeostasis, require application of the systems biology strategy at the physiological level. In vivo systems offer the possibility of investigating not only the effects of specific genetic modifications or treatments in selected tissues and organs, but also to elucidate compensatory allostatic mechanisms induced to maintain the homeostasis of the whole system. A key challenge for systems biology is to characterize different systems’ responses in the context of activated pathways. One possible strategy is based on reconstruction of tissue specific pathways using lipidomics, or metabolomics in general, in combination with proteomic and transcriptomic profiles. This approach was applied to obese mouse model and revealed activation of multiple liver pathways that may lead to metabolic products, which may impair insulin sensitivity.
Lipids play an important role as structural components (e.g., cell membranes), energy storage components (triglycerides in adipose tissue), and as signalling molecules (Vance & Vance, 2004). For example, changes in lipid function due to peroxidation, imbalanced fatty acid composition or their increased flux to peripheral tissues may contribute to development of disorders such as atherosclerosis, diabetes, metabolic syndrome or Alzheimer’s disease (Watson, 2006; Wenk, 2005). Traditional clinical lipid measures quantify total amounts of triglycerides, cholesterol, or lipoproteins. However, serum lipid profile is much more complex at the molecular level. However, the modern lipidomics and metabolomics platforms enable quantitative characterization of 100s of diverse lipid molecular species across multiple lipid classes such as sphingolipids, phospholipids, sterol esters, and acylglycerols. In most cases, exact fatty acid composition for each detected lipid can be determined.
Lipid metabolism is regulated both by genetic and environmental factors. For example, using a unique monozygous twin study design in which young adult obese monozygous twins were compared with their non-obese co-twins, we have recently shown that that obesity already in its early stages and independent of genetic influences is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance (Pietiläinen et al., 2007). The study also demonstrated the sensitivity of the metabolomics platforms since subtle pathophysiological changes were detected well prior to changes in commonly utilized clinical measures. Of special interest and clinical relevance was the finding that the atherogenic lipid profile of the obese co-twins was associated with whole body insulin resistance, something that could not be detected using classical lipid measures and inflammatory markers only.
Key Terms in this Chapter
Ceramide: Sphingolipid which can induce apoptosis and is a key mediator of lipotoxicity. It consists of sphingosine linked to fatty acid via an amide bond. Structural and signaling molecule.
Lipids: A diverse class of biological molecules that play a central role as structural components of biological membranes, energy reserves, and signaling molecules. They are broadly defined as hydrophobic or amphipathic small molecules that may originate entirely or in part by carbanion based condensation of thioesters, and/or by carbocation based condensation of isoprene units.
Pathway Instantiation: Reconstruction of possible activated pathways, originating from a specific molecular entity ( e.g. , protein or metabolite). based on molecular interactions and enzymatic reactions.
Metabolomics: Metabolomics is a discipline dedicated to the global study of small molecules ( i.e. , metabolites), their dynamics, composition, interactions, and responses to interventions or to changes in their environment, in cells, tissues, and biofluids .
Adipose Tissue: Loose connective tissue composed of fat cells or adipocytes. Its main role is to store energy in the form of fat, although it also cushions and insulates the body.
Lipotoxicity: Accumulation of (lipo)toxic reactive lipids such as ceramides in non-adipose tissues of metabolically important organs such as pancreatic ß-cells, skeletal muscle, liver, and heart.
Lipidomics: Lipidomics as a subfield of metabolomics aims at characterization of lipid molecular species and their biological roles with respect to the expression of proteins involved in lipid metabolism and function including gene regulation.
Allostasis: The process of achieving stability, or homeostasis, through physiological or behavioral change. Allostasis is generally adaptive in short term, and can be carried out, e.g. , by cytokines, autonomic nervous system, or metabolome.