Obesity has become a global public health problem: according to the World Health Organization, 39% of adults were overweight in 2014, including 13% who were obese—proportions that have doubled since 1980. It increases the risk of cardiovascular disease, type 2 diabetes and metabolic syndrome. The liver, which controls both glucose and lipid homeostasis, lies at the heart of these disorders: in the setting of insulin resistance, it continues to produce glucose, while triglycerides accumulate in hepatocytes to the point of steatosis.
This article in the News section presents work devoted to PiT1, a membrane protein first described as a retrovirus receptor and subsequently as a sodium–phosphate cotransporter. Other roles, independent of transport, were later attributed to it: cell proliferation and adhesion, TNF-α-induced apoptosis, and red blood cell differentiation. Its complete deletion is lethal in the mouse embryo at around 12.5 days of gestation, with anemia and apoptosis of the liver, which is then the main hematopoietic organ. To investigate its role in the adult liver, the team therefore inactivated the gene in hepatocytes alone, using the Cre-lox system placed under the control of the albumin promoter.
Mice lacking PiT1 in the liver gain less weight and accumulate less adipose tissue, with no imbalance between food intake and energy expenditure. They make greater use of carbohydrates as an energy source, which contributes to their fasting hypoglycemia, while their hepatic glucose production remains normal. They display improved glucose tolerance and greater insulin sensitivity, with enhanced phosphorylation of the insulin receptor, AKT and GSK3. In embryonic fibroblasts lacking PiT1, insulin signaling is prolonged: the adaptor protein IRS1 is less phosphorylated on its serine and threonine residues, less ubiquitinated and degraded more slowly, thereby delaying negative feedback. This connection is mediated by USP7, a deubiquitinating enzyme that protects IRS1: in the absence of PiT1, the USP7–IRS1 complex no longer dissociates in response to insulin, and the phosphatase PTEN associates less with IRS1. Re-expression of PiT1, even in a form unable to transport phosphate, or silencing of USP7 restores normal cell behavior.
When placed on a diet rich in fat and fructose, the knockout mice become neither obese nor diabetic. They do not accumulate inflamed visceral fat, their liver remains free of steatosis, and hepatic markers of inflammation, fibrosis and cytolysis—which are elevated in control mice—remain stable. This protection relies on reduced fatty acid uptake into hepatocytes and on a decrease in lipogenic enzymes, including the transcription factor SREBP1c. PiT1 thus emerges as a potential therapeutic target in metabolic syndrome, diabetes and obesity.