Abstract
Petite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 ablation alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females did not show obesity-induced alterations in fasting blood glucose and glucose clearance. WD-fed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased expression of inflammation-associated genes in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.
Highlights
The increasing prevalence of obesity is a global public health problem, which has been striking among children and adolescents in both developed and developing countries [1]
As the weight of Western diet (WD)-fed Petite Integration Factor 1 (PIF1) knock out (KO) females diverged from wild type (WT) females, we focused exclusively on the female cohort in subsequent experiments
While we have previously shown that Petite Integration Frequency 1 helicase knockout (PIF1 KO) mice gain weight on a regular chow diet, it was not known whether PIF1 KO mice develop metabolic alterations under WD-induced weight gain
Summary
The increasing prevalence of obesity is a global public health problem, which has been striking among children and adolescents in both developed and developing countries [1]. Clinical complications of obesity include metabolic syndrome, which can progress to type 2 diabetes mellitus (T2DM) and cardiovascular disease. Current understanding of the genes involved in obesity is limited, despite its high heritability [2]. 90% of patients with T2DM are overweight or obese. While being overweight greatly increases the likelihood of developing T2DM [3], only a subset of obese individuals acquires T2DM. Factors such as tissue inflammation that drive obesity or that determine the diabetic phenotype in obese individuals are poorly understood
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