With a focus on therapeutics, studies delineating the differential responsiveness of PPARγ mutants to endogenous and synthetic ligands has illustrated the potential for pharmacogenetics to inform therapeutic decisions in lipodystrophy related to PPARG mutations, whereas robust human studies have provided insight into the food independent metabolic effects of leptin in lipodystrophy.
A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism.
Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia.
The aim of this review is to summarize evidence linking lipodystrophy with hepatic disease and to provide a special focus on potential therapeutic perspectives of leptin replacement therapy and adiponectin upregulation in lipodystrophy.
While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy.
Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity.
Lipodystrophy was only associated with increased macrophage infiltration (P = .04) and adiponectin messenger ribonucleic acid ([mRNA] P = .008), whereas metabolic syndrome was associated with larger adipocytes (P < .0001), decreased expression of genes related to adipogenesis and adipocyte function (P values between <.0001 and .08), increased leptin mRNA (P = .04), and a trend towards increased expression of inflammatory genes (P values between .08 and .6).
This and several other long-term studies demonstrated important benefits of recombinant human leptin (metreleptin) to treat metabolic abnormalities of lipodystrophy.
Leptin has been shown to influence puberty, pregnancy, hypothalamic amenorrhea, and lipodystrophy, and with a potential therapeutic role for both metabolic and reproductive health.
The mean number of corpora lutea per ovary was significantly lower in saline-treated LD animals compared to non-LD controls (p < 0.01) and was restored to non-LD control levels by leptin (p < 0.05).
Circulating levels of AFABP and EFABP are not decreased in LD despite adipose tissue loss in contrast to other adipokines including leptin and adiponectin.
Increased expression of inflammatory genes and decreased leptin expression also occur in Cnot3<sup>ad-/-</sup> WAT, achieving levels similar to those in lipodystrophic aP2-nSrebp1c and Pparg<sup>ldi/+</sup> mice; thus, Cnot3<sup>ad-/-</sup> mice exhibit lipodystrophy.
The effect of recombinant leptin (metreleptin) therapy on facial soft tissue volume in patients with non-human immunodeficiency virus LD has not been quantified to date.
We herein focus on the cross-regulation of fat and bone and propose that marrow fat accumulation and reduced serum leptin and adiponectin levels may play important roles in the pathophysiologic process of osteoporosis in patients with lipodystrophy.
Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.
Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin.
Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial.We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency.
Leptin is not able to treat typical obesity; however, it is effective for reversing leptin deficiency-induced obesity and is possibly useful in lipodystrophy.