Serum concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) are elevated in several cardio-metabolic and inflammatory diseases. LRG1 also plays an important role in the development of hepatic steatosis and insulin resistance. In lipodystrophies (LDs), severe cardio-metabolic complications can be observed. The dysregulation of several adipokines plays a significant role in the clinical manifestation of this syndrome. To date, there have been no studies of LRG1 levels in non-HIV-LD patients. We performed a cross-sectional analysis of LRG1 serum levels in 60 patients with non-HIV-associated LD and in 60 age-, sex-, and BMI-matched healthy controls. Furthermore, we investigated the gene expression of Lrg1 in a mouse model of generalised LD. No significant difference was found in the median concentration of LRG1 serum levels between LD patients (18.2 ng/L; interquartile range 8.3 ng/L) and healthy controls (17.8 ng/L; interquartile range 11.0 ng/L). LRG1 serum concentrations correlated positively with CRP serum levels (p < 0.001). Lrg1 mRNA expression was downregulated in the adipose tissue, whereas in the liver, no difference in Lrg1 expression between LD and wild-type mice was detected. In summary, circulating levels of LRG1 are associated with low-grade inflammation but cannot distinguish between patients with LD and controls.

Lipodystrophies (LDs) are rare disorders characterized by the partial or complete loss of subcutaneous adipose tissue, leading to severe metabolic complications. Although metreleptin therapy has shown beneficial effects, its therapeutic efficacy is limited, particularly in patients with partial LD. Neuregulin 4 (NRG4), a batokine secreted by brown adipose tissue, regulates lipid metabolism and hepatic function, but its relevance in LD has not been investigated. In this study, we observed significantly reduced serum NRG4 levels in patients with LD compared to matched healthy controls. NRG4 levels declined further during metreleptin therapy, potentially reflecting fat mass reduction or limited treatment response. To explore functional relevance, we treated a transgenic LD mouse model with recombinant NRG4. While NRG4 enhanced thermogenic gene expression in brown and inguinal white adipose tissue, it did not improve systemic metabolic parameters or hepatic steatosis. In vitro, NRG4 failed to rescue impaired adipogenesis and thermogenesis in brown adipocytes from LD mice but increased insulin-stimulated fatty acid uptake in white adipocytes, indicating a preserved functional response despite differentiation defects. NRG4 also activated hepatic AMPK signaling without improving lipid accumulation. These findings suggest that NRG4 promotes adipose tissue remodeling but is insufficient to restore systemic metabolic homeostasis in LD. Together, our data indicate that NRG4's beneficial effects may depend on the presence of functional adipose tissue, which is profoundly impaired in LD. Consequently, while NRG4 may support local plasticity in adipose tissue, it is insufficient as a therapy for metabolic restoration in LD.

A large body of research demonstrates that the maternal thyroid function during pregnancy is critical for the metabolic health of the child. This project investigates the molecular mechanisms by which a dysfunction of maternal thyroid hormone production during pregnancy affects adipose tissue differentiation and function in the offspring. Aim To study promoter methylation and expression of the leptin gene in white adipose tissue (WAT) and brown adipose tissue (BAT) of F1-F3 offspring of female mice with hypothyroidism. Methods A transgenerational mouse model was used to study effects of maternal hypothyroidism in the offspring up to the F3 generation. To induce maternal hypothyroidism, female animals (C57BL/6N) received a propylthiouracil (PTU)-containing diet for two weeks from gestation day 7. Control animals with euthyroid thyroid function obtained normal chow diet. F1-F3 offspring were comprehensively phenotyped and metabolically characterized from birth until 12 weeks of age. Differences in methylation of an upstream enhancer in the leptin promoter were detected in WAT and BAT of F1-F3 offspring. Therefore, bisulfite-converted DNA was amplified by PCR and the degree of methylation was determined by pyrosequencing. In parallel to methylation, leptin mRNA expression in BAT and WAT and leptin serum levels were measured. Result We detected differences in the methylation of the promoter, gene expression and secretion of leptin between offspring of euthyroid and hypothyroid mothers in BAT and SAT, that were partially sex-specific. Conclusion Our results provide new insights into the importance of maternal thyroid function for the prenatal epigenetic imprinting of leptin expression in the offspring. Article published online: 02 May 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

Background The placenta, which has a low permeability for thyroid hormones (TH), is considered to be the interface between mother and fetus. The inhibition of maternal TH production leads to severe hypothyroidism in the offspring, since the fetal thyroid gland cannot produce TH hormones on its own until 20 weeks of gestation. Several studies have reported the strong link between thyroid dysfunctions, obesity and metabolic disorders like diabetes mellitus. Furthermore, a number of epigenetic markers have been identified that regulate glucose tolerance and insulin sensitivity. Aim To study glucose tolerance and insulin sensitivity on of F1-F3 offspring of female mice with hypothyroidism. Methods A transgenerational mouse model was used to study effects of maternal hypothyroidism in offspring of both sexes up to the F3 generation. To induce maternal hypothyroidism, female animals (C57BL/6N) received a propylthiouracil (PTU)-containing diet for two weeks from gestation day 7. Control animals with euthyroid thyroid function obtained normal chow diet. F1-F3 offspring were comprehensively phenotyped and metabolically characterized from birth until 12 weeks of age. To this aim, indirect calorimetry, glucose and insulin tolerance tests, gene expression analysis as well as serum analysis were performed. Result We found sex-specific changes in glucose metabolism that were accompanied by changes in energy metabolism. Up to the third, generation we observed significant differences in glucose tolerance and insulin sensitivity between offspring from eu- and hypothyroid mothers. Conclusion Our results provide new insights into the importance of maternal thyroid function for glucose metabolism in the offspring. Article published online: 02 May 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany