Daily Endocrinology Research Analysis

BACKGROUND: Pharmacotherapy offers a potential solution for individuals with overweight and obesity to decrease their body weight. However, there is limited knowledge of the effects of antiobesity agents on the distribution of body fat. METHODS: The PubMed, Embase, and Cochrane Library databases were reviewed for randomized controlled trials (RCTs) of weight-lowering drugs between inception and May 23, 2023. The main results were visceral and subcutaneous adipose tissue (VAT and SAT). Secondary outcomes were altered body weights and waist circumferences. For the statistical analysis, STATA 14.0 was utilized, and the frequentist method was used for random-effect network meta-analyses. RESULTS: A total of 39 articles including 41 RCTs with 2741 patients were included. GLP-1 receptor agonists and SGLT-2 inhibitors were observed to lower VAT (-0.90 [-1.32 to -0.47] and -0.66 [-1.22 to -0.10]) after a mean of 29.4 weeks, whereas only GLP-1 receptor agonists reduced SAT (-1.01 [-1.58 to -0.43]). Naltrexone-bupropion, GLP-1 receptor agonists, SGLT-2 inhibitors, and metformin were found to reduce body weight (-5.60 [-8.64 to -2.56] kg, -4.73 [-5.58 to -3.88] kg, -3.20 [-4.69 to -1.72] kg, and -1.93 [-3.01 to -0.85] kg). Lastly, waist circumference was decreased by GLP-1 receptor agonists, metformin, SGLT-2 inhibitors, and naltrexone-bupropion. CONCLUSION: This analysis demonstrated that GLP-1 receptor agonists may have advantages over other antiobesity agents in reducing VAT and SAT. SGLT-2 inhibitors were more helpful to reduce VAT. The clinical significance relates to physicians being able to choose appropriate weight-loss agents in accordance with a patient's fat distribution.

Hereditary paragangliomas (PGLs) caused by germline SDHD pathogenic variants (PVs) exhibit a parent-of-origin effect, with tumors arising almost exclusively when the PV is inherited from the paternal allele. The Hensen model proposes that a cluster of maternally expressed tumor suppressor genes (TSGs) on chromosome 11p15.5 may play a crucial role in SDHD-related PGL tumorigenesis, wherein somatic loss of maternal 11p and wild-type SDHD allele, in conjunction with a paternally inherited SDHD PV, triggers tumor development. To systematically localize and identify the most crucial maternal-expressed TSGs within 11p15.5, we developed a novel single nucleotide variant (SNV)-oriented, capture-based targeted enrichment approach followed by next-generation sequencing (NGS) to enable high-resolution loss-of-heterozygosity (LOH) analysis. Among 13 SDHD-related PGLs and 23 non-SDHD-related PGLs, a somatic loss of 11p15.5-15.4 was detected in 92% and 47%, respectively, a significant difference (p = 0.0035). Parental genotype analysis confirmed that the lost chromosome was of maternal origin. In our studies, 12/13 SDHD-related tumors demonstrated complete loss of the maternal 11p15.5-15.4 region, preventing localization of a specific driver TSG. Only one exceptional SDHD-related tumor retained this region, warranting further investigation into the mechanism underlying parent-of-origin tumorigenesis.

Ghrelin acts via the growth hormone secretagogue receptor (GHSR), and increases both food intake and growth hormone (GH) secretion. Studies in mice with genetic manipulations of GH receptor (GHR) revealed that GH action is required for ghrelin's orexigenic effects. However, the biological basis of this interdependence remains unclear. Here, we studied the mechanisms by which GHR contributes to ghrelin-induced hyperphagia in male mice. Transcriptomic analyses of single-cell datasets revealed that Ghr and Ghsr are co-expressed in a small subset of neurons, particularly within the hypothalamic arcuate nucleus (ARH). Systemic ghrelin administration increased food intake, circulating GH, and glycemia, but did not induce GHR activation in the brain, as indicated by the absence of pSTAT5 immunoreactivity. Central GH administration failed to enhance ghrelin-induced food intake or glycemia. To evaluate the role of peripheral GHR signaling, we treated mice with the brain-impermeable GHR antagonist pegvisomant. Systemically-injected pegvisomant impaired ghrelin's orexigenic effect without affecting its impact on glycemia or hypothalamic c-Fos activation, indicating that peripheral GHR signaling is required for ghrelin-induced hyperphagia. Pegvisomant did not alter refeeding-induced or AgRP neuron-mediated hyperphagia, suggesting a selective blockade of ghrelin's action. Moreover, ghrelin-induced food intake was preserved in hepatocyte-specific GHR knockout mice, despite disrupted hepatic GH signaling. Thus, peripheral, non-hepatic GHR signaling is selectively required for the orexigenic effects of ghrelin. This work reveals a critical GH-dependent, liver-independent mechanism underlying ghrelin-driven feeding, with potential implications for the neuroendocrine regulation of appetite and for therapeutic strategies targeting the ghrelin-GH axis in metabolic diseases.