Lack of maternal exposure to somatostatin (Sst) induces severe insulin resistance and obesity with leptin resistance in male offspring fed a high-fat diet

Authors: YANG, ZHONGYUE - University Of California, Davis; Kirschke-Schneide, Catherine; Huang, Liping

Submitted to: Journal of Molecular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/11/2025
Publication Date: N/A
Citation: N/A

Interpretive Summary: Somatostatin (Sst) is a negative regulator of many hormones, including insulin and glucagon. The prenatal environment impacts offspring’s risk to type 2 diabetes in adulthood. However, the effect of maternal Sst deficiency on offspring’ glucose and insulin metabolism have been poorly addressed. The goal of this study was to investigate the impact of the lack of maternal Sst exposure in mouse offspring on diet-induced changes in glucose metabolism and adiposity. Sst knockout offspring born to Sst-heterozygous dams (SstKO) or to Sst-homozygous dams (SstKO-MSD) were fed either a regular chow diet (CD) or a high-fat diet (HFD) at 3-week-old for 15 weeks. Body weight and blood glucose levels were monitored. Glucose and insulin tolerance tests were performed. Plasma hormone levels and gene expression in the hypothalamus were investigated. The results demonstrated that male SstKO-MSD offspring developed obesity accompanied by severe insulin and leptin resistance after HFD challenge. Insulin secretion was reduced in both basal and oral glucose-challenged conditions in CD-fed SstKO-MSD mice. A reduced ratio of islet area to the pancreas area was noted in SstKO-MSD mice. Plasma levels of glucagon, Glp1, and Pyy were elevated in both SstKO and SstKO-MSD mice. mRNA expression of leptin receptor, Foxo1, Npy, and Agrp was down-regulated in male SstKO-MSD and SstKO mice fed HFD. These results demonstrate that lack of Sst exposure in the uterus impairs the islet development in offspring and increases risks of diet-induced obesity and insulin resistance as well as leptin resistance later in life.

Technical Abstract: Somatostatin (Sst) is a peptide hormone secreted from the stomach. It is a negative regulator of many other hormones, such as insulin (acting to reduce blood glucose after food intake) and glucagon (acting to increase blood glucose during fasting). The prenatal environment impacts offspring’s risk to type 2 diabetes in adulthood. However, the effect of maternal Sst deficiency on offspring’ glucose and insulin metabolism have been poorly addressed. The goal of this study was to investigate the impact of the lack of maternal Sst exposure in mouse offspring on diet-induced changes in glucose metabolism and adiposity. We fed the SstKO offspring (pups without an intact Sst gene in the genome) born to Sst-heterozygous dams or the SstKO-MSD offspring from Sst-homozygous dams either a regular chow diet (CD) or a high-fat diet (HFD) at 3-week-old for 15 weeks. Body weight and blood glucose levels were monitored. Glucose and insulin tolerance tests were performed. Plasma hormone levels and gene expression in the hypothalamus of the brain were investigated. We found that male SstKO-MSD offspring developed obesity accompanied by severe insulin and leptin resistance after HFD challenge. Leptin is a peptide hormone secreted from fat cells which controls food intake through its action on the brain to inhibit homeostatic feeding and food reward. Insulin secretion was reduced in both basal and oral glucose-challenged conditions in CD-fed SstKO-MSD mice. A reduced ratio of islet area to the pancreas area was noted in SstKO-MSD mice. Plasma levels of glucagon, Glp1 (glucagon-like peptide 1, a peptide hormone acting to stimulate insulin secretion in a glucose-dependent manner), and Pyy (peptide YY, a peptide hormone regulating appetite) were elevated in both SstKO and SstKO-MSD mice. mRNA expression of leptin receptor, Foxo1 (forkhead box O1, a transcription factor activates metabolic related gene expression leading to food intake), Npy (neuropeptide Y, a peptide hormone regulating food intake and energy expenditure) and Agrp (agouti related neuropeptide playing a role in weight regulation) was down-regulated in male SstKO-MSD and SstKO mice fed HFD. We concluded these results demonstrate that lack of Sst exposure in the uterus impairs the islet development in offspring and increases risks of diet-induced obesity and insulin resistance as well as leptin resistance later in life.