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Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding
Merly C Vogt1, Lars Paeger2, Simon Hess2
1Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany.
Insights
Maternal high-fat diet during lactation programs offspring for obesity by disrupting hypothalamic neural projections. Restoring insulin signaling in offspring neurons prevents these metabolic disruptions.
Area of Science:
- Neuroscience
- Metabolic Research
- Developmental Biology
Background:
- Maternal metabolic health significantly impacts offspring's long-term health.
- High-fat diets (HFD) during critical developmental windows can lead to metabolic dysfunction.
Purpose of the Study:
- To investigate how maternal HFD during lactation affects offspring's metabolic homeostasis and hypothalamic circuitry.
- To identify the role of insulin signaling in mediating these effects.
Main Methods:
- Mice were fed a HFD during lactation.
- Assessed offspring for obesity and glucose homeostasis.
- Analyzed hypothalamic melanocortin circuitry, including proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons and their projections.
- Utilized genetic manipulation to abrogate insulin action in POMC neurons.
Main Results:
- Maternal HFD during lactation led to offspring obesity and impaired glucose homeostasis.
- Hypothalamic POMC and AgRP neuronal function and expression were unaffected, but their projections were impaired.
- Abrogating insulin action in offspring POMC neurons prevented altered projections and metabolic deficits.
Conclusions:
- Maternal HFD during lactation disrupts offspring metabolic homeostasis by impairing hypothalamic neuronal projections.
- Insulin signaling in offspring POMC neurons is crucial for preventing metabolic dysfunction induced by maternal overnutrition.
Abstract:
Maternal metabolic homeostasis exerts long-term effects on the offspring's health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.
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