Human Loss-of-Function<i> ZNRF3</i> Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion

<jats:p>&lt;p dir="ltr"&gt;&lt;i&gt;Z&lt;/i&gt;&lt;i&gt;inc and ring finger protein 3 (ZNRF3)&lt;/i&gt; functions as a transmembrane E3 ubiquitin ligase. Although genome-wide association studies have implicated &lt;i&gt;ZNRF3&lt;/i&gt; in body fat distribution, the evidence from human genetics and animal models has been lacking. Here, through whole-exome sequencing of 1,944 obese cases and 2,161 healthy lean controls, we identified a rare loss-of-function mutation in human &lt;i&gt;ZNRF3&lt;/i&gt; (p.V228L) observed exclusively in eight obese subjects. &lt;a href="" target="_blank"&gt;These carriers exhibit increased hip circumference and subcutaneous fat area, and lower fasting glucose levels compared with non-carriers.&lt;/a&gt; In mice, adipocyte-specific &lt;i&gt;Znrf3&lt;/i&gt; deletion leads to progressive adiposity, with expansion of subcutaneous white adipose tissue (sWAT), and improved glucose tolerance after a long-term high-fat diet. Furthermore, &lt;i&gt;Znrf3&lt;/i&gt; deficiency impairs the browning capacity of sWAT and cold-induced thermogenesis. A knock-in mouse model harboring the homologous human p.V228L mutation recapitulates key features of carriers and knockout mice, including reduced sWAT thermogenic function, altered fat distribution, and improved glucose tolerance. Mechanistically,&lt;a href="" target="_blank"&gt; &lt;i&gt;Znrf3&lt;/i&gt; &lt;/a&gt;loss attenuates the cAMP/PKA signaling pathway, suppressing UCP1 expression&lt;a href="" target="_blank"&gt; and mitochondrial respiration.&lt;/a&gt; Collectively, these findings provide genetic and biological evidence that &lt;i&gt;ZNRF3&lt;/i&gt; regulates thermogenic capacity and remodeling of sWAT, offering new insights into obesity heterogeneity.&lt;/p&gt;</jats:p>