Decreased PPARγ expression compromises perigonadal-specific fat deposition and insulin sensitivity

Mutations and polymorphisms in PPARG have been linked to adiposity and partial lipodystrophy in humans. However, how disturbances in PPARG lead to depot-specific effects on adipose tissue, as shown by the characteristic aberrant fat distribution in patients, remains unclear. By manipulating the 3′-untranslated region of the Pparg gene, we have generated mice with peroxisome proliferator-activated receptor γ (PPARγ) gene expression ranging from 25% to 100% normal. Basal levels of PPARγ transcripts between 50% and approximately 100% had no significant effect on body weight, fat mass, and insulin sensitivity. In contrast, mice with 25% normal PPARγ expression exhibited reduced body weight and total fat mass, insulin resistance, and dyslipidemia. Interestingly, fat mass was selectively reduced in perigonadal depot without significant changes in inguinal and other depots. Expression of adipogenic factor CCAAT enhancer binding protein-α and some other metabolic genes containing peroxisome proliferator response element were reduced in a perigonadal depot-specific fashion. This was further associated with depot-specific reduction in the expression of adipokines, increased expression of TNFα, and increased ectopic lipid deposition in muscles. Together, these results underscore the differential sensitivity of the individual fat depots on PPARγ availability as an underlying mechanism of partial lipodystrophy.