Mice Deficient in <i>Sfrp1</i> Exhibit Increased Adiposity, Dysregulated Glucose Metabolism, and Enhanced Macrophage Infiltration

<div><p>The molecular mechanisms involved in the development of obesity and related complications remain unclear. Wnt signaling plays an important role in preadipocyte differentiation and adipogenesis. The expression of a Wnt antagonist, secreted frizzled related protein 1 (SFRP1), is increased in response to initial weight gain, then levels are reduced under conditions of extreme obesity in both humans and animals. Here we report that loss of <i>Sfrp1</i> exacerbates weight gain, glucose homeostasis and inflammation in mice in response to diet induced obesity (DIO). Sfrp1^-/- mice fed a high fat diet (HFD) exhibited an increase in body mass accompanied by increases in body fat percentage, visceral white adipose tissue (WAT) mass, and adipocyte size. Moreover, <i>Sfrp1</i> deficiency increases the mRNA levels of key <i>de novo</i> lipid synthesis genes (<i>Fasn</i>, <i>Acaca</i>, <i>Acly</i>, <i>Elovl</i>, <i>Scd1</i>) and the transcription factors that regulate their expression (<i>Lxr-α, Srebp1, Chreb</i>, and <i>Nr1h3</i>) in WAT. Fasting glucose levels are elevated, glucose clearance is impaired, hepatic gluconeogenesis regulators are aberrantly upregulated (<i>G6pc</i> and <i>Pck1</i>), and glucose transporters are repressed (<i>Slc2a2</i> and <i>Slc2a4</i>) in Sfrp1^-/- mice fed a HFD. Additionally, we observed increased steatosis in the livers of Sfrp1^-/- mice. When there is an expansion of adipose tissue there is a sustained inflammatory response accompanied by adipokine dysregulation, which leads to chronic subclinical inflammation. Thus, we assessed the inflammatory state of different tissues and revealed that Sfrp1^-/- mice fed a HFD exhibited increased macrophage infiltration and expression of pro-inflammatory markers including <i>IL-6, Nmnat, Tgf-β2</i>, and <i>SerpinE1</i>. Our findings demonstrate that the expression of <i>Sfrp1</i> is a critical factor required for maintaining appropriate cellular signaling in response to the onset of obesity.</p>