Human Metabolic Syndrome Resulting From Dominant-Negative Mutations in the Nuclear Receptor Peroxisome Proliferator-Activated Receptor-γ

Abstract

We previously reported a syndrome of severe hyperinsulinemia and early-onset hypertension in three patients with dominant-negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-␥. We now report the results of further detailed pathophysiological evaluation of these subjects, the identification of affected prepubertal children within one of the original families, and the effects of thiazolidinedione therapy in two subjects. These studies 1) definitively demonstrate the presence of severe peripheral and hepatic insulin resistance in the affected subjects; 2) describe a stereotyped pattern of partial lipodystrophy associated with all the features of the metabolic syndrome and nonalcoholic steatohepatitis; 3) document abnormalities in the in vivo function of remaining adipose tissue, including the inability of subcutaneous abdominal adipose tissue to trap and store free fatty acids postprandially and the presence of very low circulating levels of adiponectin; 4) document the presence of severe hyperinsulinemia in prepubertal carriers of the proline-467-leucine (P467L) PPAR-␥ mutation; 5) provide the first direct evidence of cellular resistance to PPAR-␥ agonists in mononuclear cells derived from the patients; and 6) report on the metabolic response to thiazolidinedione therapy in two affected subjects. Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-␥ can provide important insight into the roles of this nuclear receptor in human metabolism. Diabetes 52:910 -917, 2003

Fat poetry: a kingdom for PPARγ

“…These adults also suffered from lipodystrophy at the extremities, elevated plasma TG concentrations, hyperinsulinemia, and fat accumulation in the liver. However, there was no difference in the circulating levels of leptin and TNF-α but a decrease in adiponectin levels in the two PPARgP467L patients [191]. In vitro studies of both mutations suggest a destabilization of the PPARg configuration more favorable for receptor-corepressor interactions with dominant-negative properties.…”

Lessons from human mutations in PPARγ

“…A man with PPARg P467L treated for 6 months with 8 mg daily of rosiglitazone had increased fat mass, increased adipocytokine concentrations and normalized glycemia. 28 In contrast, a woman with PPARg V290M treated for 6 months with 8 mg daily of rosiglitazone had a less apparent response of anthropometric and glycemic variables to TZD. 28 A woman with PPARg F388L did not respond to 8 mg daily of rosiglitazone, but her glycemia improved over 12 weeks with 16 mg daily of rosiglitazone.…”

“…28 In contrast, a woman with PPARg V290M treated for 6 months with 8 mg daily of rosiglitazone had a less apparent response of anthropometric and glycemic variables to TZD. 28 A woman with PPARg F388L did not respond to 8 mg daily of rosiglitazone, but her glycemia improved over 12 weeks with 16 mg daily of rosiglitazone. Thus, subjects with both molecular lipodystrophy types respond to TZD, with perhaps a better response in the LMNA form.…”

“…27 However, later re-evaluation of subjects with PPARg V290M or P467L showed loss of subcutaneous limb fat and atrophy of buttock fat, confirming that mutant PPARg causes lipodystrophy. 28 Heterozygosity for PPARg R425C was found in another patient who was ascertained based on a clinical diagnosis of partial lipodystrophy. 29 However, PPARg R425C was not assessed and there was no demonstration of germline transmission.…”

Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

“…PPARG heterodimerises with the retinoid X receptor (RXR) following ligand binding and this complex can activate the PPARG response element (PPRE) that controls several genes of great importance for insulin sensitivity. Dominant negative mutations of PPARG have been found in subjects that are severely insulinresistant and who also develop type 2 diabetes at an early age [13,14], demonstrating the importance of PPARG signalling for normal insulin sensitivity in humans. Conversely, treatment with synthetic PPARG activators of the thiazolidinediones class, such as rosiglitazone and pioglitazone, is currently a treatment option in patients with type 2 diabetes.…”