👤 M Frydman

The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation antiobesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects. Show less

Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity Show less

Phthalates have been shown to have reprotoxic effects in rodents and human during fetal life. Previous studies indicate that some members of the nuclear receptor (NR) superfamilly potentially mediate phthalate effects. This study aimed to assess if expression of these nuclear receptors are modulated in the response to MEHP exposure on the human fetal gonads in vitro. Testes and ovaries from 7 to 12 gestational weeks human fetuses were exposed to 10(-4)M MEHP for 72 h in vitro. Transcriptional level of NRs and of downstream genes was then investigated using TLDA (TaqMan Low Density Array) and qPCR approaches. To determine whether somatic or germ cells of the testis are involved in the response to MEHP exposure, we developed a highly efficient cytometric germ cell sorting approach. In vitro exposure of fetal testes and ovaries to MEHP up-regulated the expression of LXRα, SREBP members and of downstream genes involved in the lipid and cholesterol synthesis in the whole gonad. In sorted testicular cells, this effect is only observable in somatic cells but not in the gonocytes. Moreover, the germ cell loss induced by MEHP exposure, that we previously described, is restricted to the male gonad as oogonia density is not affected in vitro. We evidenced for the first time that phthalate increases the levels of mRNA for LXRα, and SREBP members potentially deregulating lipids/cholesterol synthesis in human fetal gonads. Interestingly, this novel effect is observable in both male and female whereas the germ cell apoptosis is restricted to the male gonad. Furthermore, we presented here a novel and potentially very useful flow cytometric cell sorting method to analyse molecular changes in germ cells versus somatic cells. Show less

The Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II, TRPS II) is characterized by craniofacial dysmorphism and skeletal abnormalities. It combines the clinical features of TRPS I and multiple cartilaginous exostoses (EXT). We have used YAC cloning, Southern blotting, PCR analysis, and fluorescence in situ hybridization to study chromosome 8 deletions, translocations, an inversion, and an insertion in patients with TRPS I, TRPS II or EXT. Our results indicate that the TRPS gene maps more than 1,000 kb proximal to the EXT1 gene and that both genes are affected in TRPS II. We conclude that TRPS II is not due to pleiotropic effects of mutations in a single gene, but that it is a true contiguous gene syndrome. Show less