PTEN: A Thrifty Gene Leads to obesity and Insulin resistance During Prosperous Times

The modern obesity epidemic and its associated disorders, including metabolic issues and cancer, have been linked to "thrifty genes." Historically, these genes enhanced energy efficiency and fat storage to help organisms survive famines. However, in today's environment, these genes have become harmful. 

The researchers of the present study proposed PTEN as a key gene involved in obesity and insulin resistance due to its roles in metabolism, cancer, and reproduction. PTEN activity can be influenced in utero by nutrient availability through the methylation arm of the epigenetic pathway. Additionally, protein and choline deficiencies have been shown to upregulate DNA methyltransferases (DNMTs), specifically DNMT1 and DNMT3a, which can methylate the PTEN promoter region and suppress its expression. 

Consequently, PTEN acts like a metabolic rheostat, adjusting its activity based on nutrient availability. This resultant “dose” of the protein impacts the insulin-PI3K/AKT/mTOR pathway, which controls energy usage and cell proliferation. The metabolic capacity of the organism is thus "fixed" around conception to match a specific postnatal nutritional environment. However, when there is a mismatch between this pre-set metabolic capacity and the actual postnatal environment, it can lead to obesity-related diseases.

Source: Venniyoor A. PTEN: A Thrifty Gene That Causes Disease in Times of Plenty? Front Nutr. 2020 Jun 5;7:81. doi: 10.3389/fnut.2020.00081. Erratum in: Front Nutr. 2020 Nov 17;7:573536. doi: 10.3389/fnut.2020.573536. PMID: 32582754; PMCID: PMC7290048.