Maternal Diabetes Compromises the Organization of Hypothalamic Feeding Circuits and Impairs Leptin Sensitivity in Offspring
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Maternal diabetes is a common complication of pregnancy, and the offspring of diabetic mothers have a higher risk of developing obesity and type 2 diabetes later in life. Despite these observations, the precise biological processes mediating this metabolic programming are not well understood. Here, we explored the consequences of maternal diabetes on the organization of hypothalamic neural circuits involved in the regulation of energy balance. To accomplish this aim, we used a mouse model of maternal insulin deficiency induced by streptozotocin injections. Maternal diabetes was found to be associated with changes in offspring growth as revealed by a significantly higher pre- and postweaning body weight in the offspring of insulin-deficient dams relative to those of control mice. Mice born to diabetic dams also showed increased fasting glucose levels, increased insulin levels, and increased food intake during their adult lives. These impairments in metabolic regulation were associated with leptin resistance during adulthood. Importantly, the ability of leptin to activate intracellular signaling in arcuate neurons was also significantly reduced in neonates born to diabetic dams. Furthermore, neural projections from the arcuate nucleus to the paraventricular nucleus were markedly reduced in the offspring of insulin-deficient dams. Together, these data show that insulin deficiency during gestation has long-term consequences for metabolic regulation. They also indicate that animals born to diabetic dams display abnormally organized hypothalamic feeding pathways that could result from the attenuated responsiveness of hypothalamic neurons to the neurotrophic actions of leptin during neonatal development.
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GDM exposure disrupts fetal hypothalamic development, impairing appetite regulation.
“GDM exposure disrupts fetal hypothalamic development, impairing appetite regulation.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [66]
Adult animals born to diabetic mothers had higher blood glucose and insulin levels, doubled serum leptin levels, and adipocyte hyperplasia, suggesting possible leptin resistance induced by in utero exposure to maternal hyperglycemia.
“Blood glucose and insulin levels were higher in adult animals born to diabetic mothers compared with control mice; furthermore, serum leptin levels were doubled compared to control subjects, and WAT histological analysis showed adipocyte hyperplasia, suggesting possible leptin resistance induced by in utero exposure to maternal hyperglycemia.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [66]
Both type I and type II diabetes during pregnancy increase the onset risk of diseases in offspring.
“Surprisingly, both type I and type II diabetes during pregnancy increased the onset risk of diseases in offspring.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [66]
Compromised development of hypothalamic circuits due to maternal hyperglycemia and impaired development and axonal growth of ARH neurons has been demonstrated.
“Recently, compromised development of hypothalamic circuits due to maternal hyperglycemia and impaired development and axonal growth of ARH neurons has been demonstrated [66,67,68,69,70].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [66]
In a mouse model, maternal insulin deficiency induced by STZ during pregnancy led to heavier body weights at birth that persisted into adulthood and was associated with increased food intake.
“Compared with control pups, STZ-derived pups had heavier body weights at birth, and this elevated body weight persisted into adulthood and was also associated with an increase in food intake during adulthood, suggesting that in utero exposure to hyperglycemia affects neuronal circuits involved in the regulation of hunger and satiety.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [66]
In utero exposure to hyperglycemia affects neuronal circuits involved in the regulation of hunger and satiety.
“suggesting that in utero exposure to hyperglycemia affects neuronal circuits involved in the regulation of hunger and satiety.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [66]
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- Authors
- Steculorum, S. M., & Bouret, S. G.
- Affiliations
- University of Southern California (US)
- The Saban Research Institute (S.M.S., S.G.B.), Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2011-08-23
- Volume
- 152
- Issue
- 11
- Pages
- 4171-4179
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3199015
- OpenAlex
- W2143831945
- Cited by
- 140
- References
- 41
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 3 · 2023: 11 · 2022: 9 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 12 · 2016: 11 · 2015: 13 · 2014: 10 · 2013: 13 · 2012: 15
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Southern California
- Children's Hospital Los Angeles
- Agence Nationale de la Recherche (DK84142, ANR-08-JCJC-0055)
- National Institutes of Health
- Saban Research Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (DK84142, R01DK084142)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- maternal diabetes, streptozotocin-induced diabetes, leptin resistance, arcuate nucleus, paraventricular nucleus, neonatal development, metabolic programming, offspring obesity, type 2 diabetes risk, dietary intake, fasting blood glucose, energy balance
- MeSH terms
- Adipose Tissue, Animals, Diabetes Mellitus, Type 2, Eating, Female, Hypothalamus, Insulin, Nerve Net, Neurons, Obesity, Phosphorylation, Pregnancy, Diabetes, Gestational, Leptin, Maternal Nutritional Physiological Phenomena, STAT3 Transcription Factor, Mice
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