Hypothalamic control of energy rheostasis during metabolic challenges, pregnancy, and lactation

Mammals rely on the ability of their brain to detect and respond to energetic demands changes, yet the neural circuits that allow adaptation to energy imbalance are not fully understood. The melanocortin-3 receptor (MC3R) has been shown to play an important role in energy rheostasis, with global constitutive MC3R deletion of the gene impairing behavioral responses to both orexigenic and anorexic challenges. To identify the specific brain regions and mechanisms involved in this phenotype, Chapter 2 examines MC3R function in the medial hypothalamus (MH) and dorsal medial hypothalamus (DMH) using cre-lox system mediated gene deletion, chemogenetics, and in situ hybridization in adult mice. MC3R signaling in the DMH was found to contribute to energy rheostasis, with region-specific deletion altering food intake and body weight in response to high-fat diet feeding or pharmacological anorexia, along with impairment of energy expenditure after deletion of MC3R in DMH or activation of these cells using chemogenetics. These effects were often sexually dimorphic, potentially reflecting differences in gene expression profiles of MC3R-expressing cells between males and females. The sexually dimorphic phenotype observed was further characterized with RNAscope in situ hybridization, showing that female and male MC3R cells have different transcriptional profiles in DMH. Chapters 3 and 4 investigate neural adaptations supporting the increased energy intake of pregnancy and lactation, unique metabolic states defined by increased hyperphagia. Chemogenetic manipulation, fiberphotometry, and spatial transcriptomics revealed that pregnancy increases AgRP neuron activity and decreases POMC neuron activity in the arcuate nucleus. Chemogenetic activation of POMC neurons or inhibition of AgRP neurons suppressed pregnancy-induced feeding, indicating that these changes are required for gestational hyperphagia. Spatial transcriptomic profiling, using in situ hybridization and 5000-gene Xenium panel, showed transcriptional remodeling in the arcuate nucleus during pregnancy and lactation, especially in AgRP and POMC expressing, consistent with their hyperphagic phenotype. These studies identify MC3R signaling in the DMH as a critical component of energy rheostasis and define cellular and transcriptional mechanism impaired during pregnancy and lactation which could explain their hyperphagic phenotype. Together, they provide new insight into how hypothalamic circuits adapt to distinct physiological states to regulate energy balance. Understanding these mechanisms can help address metabolic disorders with impaired energy homeostasis and guide future work on hypothalamic circuit reorganization across changing physiological demands.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Possa Paranhos, Ingrid Camila

Contributors dc:contributor

• Sweeney, Patrick
• Raetzman, Lori
• Tsai, Nien-Pei
• Liang, Nu-Chu

• MC3R
• energy homeostasis
• feeding behaviour
• melanocortin
• pregnancy
• lactation
• hypothalamus

Statement dc:rights

• Copyright 2025 Ingrid Camila Possa Paranhos

Language dc:language

en

Handle dc:identifier

https://hdl.handle.net/2142/132465

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/132465