Nutrigenomics has thus far mostly been studied by analyzing the genomics, transcriptomics, proteomics, metabolomics and phenomics of enzymes. However, the genome network of a cell is driven by both energy and information transformed by transporters and receptors. Genes for these membrane protein superfamilies occupy one of the largest groups in the human genome. Thus, in nutrigenomics, both informatics and bioenergetics represent one of the most challenging fields. In this paper, we describe pleiotropic effects of nutrients and the flow of energy and signals through membranes in both peripheral (e.g. myocytes, and adipocytes) and central (neuron) levels. Many polymorphisms of membrane transporters and receptors, such as uncoupling proteins (UCPs) and β-adrenergic receptors (β-ARs) have been associated with obesity. The peripheral fuel gauge is also associated with obesity and insulin resistance and is controlled by the hypothalamus-leptin feedback loop, biological clock and finally integrated by the cortex. These data will provide important insights into an individualized intervention to prevent metabolic syndrome by increasing rate-limiting steps of energy expenditure.