The modern obesity epidemic with associated disorders of metabolism and cancer has been attributed to the presence of "thrifty genes". In the distant past, these genes helped the organism to improve energy efficiency and store excess energy safely as fat to survive periods of famine, but in the present day obesogenic environment, have turned detrimental. I propose PTEN as the likely gene as it has functions that span metabolism, cancer and reproduction, all of which are deranged in obesity and insulin resistance. The activity of PTEN can be calibrated in utero by availability of nutrients by the methylation arm of the epigenetic pathway. Deficiency of protein and choline has been shown to upregulate DNA methyltransferases (DNMT), especially 1 and 3a; these can then methylate promoter region of PTEN and suppress its expression. Thus, the gene is tuned like a metabolic rheostat proportional to the availability of specific nutrients, and the resultant "dose" of the protein, which sits astride and negatively regulates the insulin-PI3K/AKT/mTOR pathway, decides energy usage and proliferation. This "fixes" the metabolic capacity of the organism periconceptionally to a specific postnatal level of nutrition, but when faced with a discordant environment, leads to obesity related diseases.

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Obesity is recognized as the second highest risk factor for cancer. The pathogenic mechanisms underlying tobacco-related cancers are well characterized and effective programs have led to a decline in smoking and related cancers, but there is a global epidemic of obesity without a clear understanding of how obesity causes cancer. Obesity is heterogeneous, and approximately 25% of obese individuals remain healthy (metabolically healthy obese, MHO), so which fat deposition (subcutaneous versus visceral, adipose versus ectopic) is “malignant”? What is the mechanism of carcinogenesis? Is it by metabolic dysregulation or chronic inflammation? Through which chemokines/genes/signaling pathways does adipose tissue influence carcinogenesis? Can selective inhibition of these pathways uncouple obesity from cancers? Do all obesity related cancers (ORCs) share a molecular signature? Are there common (over-lapping) genetic loci that make individuals susceptible to obesity, metabolic syndrome, and cancers? Can we identify precursor lesions of ORCs and will early intervention of high risk individuals alter the natural history? It appears unlikely that the obesity epidemic will be controlled anytime soon; answers to these questions will help to reduce the adverse effect of obesity on human condition.

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