Studies that simultaneously quantify the lipid metabolites—substrates and products of biochemical pathways—in tissues and biofluids have proven to be extremely valuable in revealing dysregulation in biochemical pathways associated with other metabolic diseases such as atherosclerosis. This chapter describes the use of comprehensive analysis of lipids associated with various biochemical pathways combined with specific dietary challenges to reveal the dynamic nature of an individual’s metabolic phenotype (German et al., 2007). Circulating lipids are derived from both diet and endogenous metabolism. These lipids are highly dynamic, interactive biological molecules that make up most cellular components and signaling molecules, and they dictate energy partitioning and control of food intake. Remarkably, although food intake is central to the problem of obesity, the vast majority of studies attempting to explain the variations in metabolism that could account for excess intake and for its metabolic consequences have examined individuals and their various physiological, metabolic, and endocrine characteristics in the fasted condition. Furthermore, studies to date have examined only a subset of the metabolites representing the various biochemical pathways that are both responsive to dietary intake and associated with energy metabolism. Both of these decisions—to largely avoid examining the fed state and to constrain metabolic interrogation to a small subset of metabolites—have severely limited the ability of studies of energy metabolism to clarify precisely how diet as a variable impacts weight regulation. Clinically, lipids are measured in the fasted condition, yet this is the period when most indices of diet and its effects on lipid metabolism are minimal. In this chapter, the principles of metabolomics are extended into two directions—input variables as food metabolite composition and output variables as the subsequent effects on post-prandial metabolism within individual humans. This approach is providing insights into the metabolic regulation associated with energy balance and obesity. The practical application of a challenge approach that measures the fluxes through specific biochemical pathways is the ability to personalize dietary recommendations based on an individual’s metabolic phenotype. We propose that this approach would have a profound impact on the long-term success of diet and lifestyle-based interventions. Not only would metabolically appropriate diet and lifestyle modification be more effective in producing measurable improvements in health, perhaps even more importantly, it would increase patient acceptance and long-term adherence. Currently, people are wary of dietary recommendations because they seem to be changing every day. One day it is “beneficial” to consume eggs, the next day it is “deleterious” to consume eggs. The truth is that for some individuals eggs are beneficial while for others the cons outweigh the pros and for them egg consumption is a net negative. If we measure with accuracy and specificity the metabolic responses of individuals to specific meals and food items, and provide clear evidence that specific dietary components are causing harm whereas others are beneficial, the acceptance of recommendations will be much higher. Instead of rigidly imposed levels of acceptable intake of foods and food components that are deleterious to the health of “the average person” individuals would be free to choose foods that are palatable and enjoyable to them in doses that are metabolically appropriate for them. The success of long-term dietary and lifestyle approaches that prevent obesity and produce weight loss will ultimately depend on the acceptability of those regimens to individuals living their normal lives.
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