Biology subjects

van Veen, J. E.

Publications and source records attributed to van Veen, J. E..

4 recordsLinked to original sources

bioRxiv2024

Sex-specific thermoregulatory effects of estrogen signaling in Reprimo lineage cells

Estrogens have considerable impact on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor alpha (ER) alters energy intake and multiple aspects of energy expenditure, effects that may be mediated by specific regions or neuronal sub-populations of the hypothalamus. This study investigates the function of ER in neurons of the lineage that expresses Rprm (Reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ER in Rprm lineage cells (Reprimo-specific estrogen receptor KO; RERKO) and report changes in core temperature in female mice, with no changes in movement or food intake. RERKO females have elevated brown adipose tissue (BAT) temperature and lower tail temperature relative to controls, suggesting increased heat production and reduced heat dissipation, respectively. Developmental expression of Rprm was detected in the brain, but not in BAT or white adipose tissue suggesting temperature changes may be mediated by the nervous system. To confirm centrally mediated effects on temperature, we ablated Rprm expressing cells in the mediobasal hypothalamus and observed a reduction in core temperature relative to controls. Taken together, these results indicate that estrogen signaling in the Rprm lineage is critical for thermoregulation, mainly through the modulation of brown adipose tissue thermogenesis in female, but not male, mice.

physiology↗

bioRxiv2023

Feeding Neurons Integrate Metabolic and Reproductive States in Mice

Trade-offs between metabolic and reproductive processes are important for survival, particularly in mammals that gestate their young. Puberty and reproduction, as energetically taxing life stages, are often gated by metabolic availability in animals with ovaries. How the nervous system coordinates these trade-offs is an active area of study. We identify somatostatin neurons of the tuberal nucleus (TNSST) as a node of the feeding circuit that alters feeding in a manner sensitive to metabolic and reproductive states in mice. Whereas chemogenetic activation of TNSST neurons increased food intake across sexes, selective ablation decreased food intake only in female mice during proestrus. Interestingly, this ablation effect was only apparent in animals with a low body mass. Fat transplantation and bioinformatics analysis of TNSST neuronal transcriptomes revealed white adipose as a key modulator of the effects of TNSST neurons on food intake. Together, these studies point to a mechanism whereby TNSST hypothalamic neurons modulate feeding by responding to varying levels of circulating estrogens differentially based on energy stores. This research provides insight into how neural circuits integrate reproductive and metabolic signals, and illustrates how gonadal steroid modulation of neuronal circuits can be context-dependent and gated by metabolic status.

neuroscience↗

bioRxiv2020

Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ER), as conditional knockout of ER in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ER-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ER mediates several key side effects of tamoxifen therapy.

neuroscience↗

bioRxiv2019

Single cell profiling of the VMH reveals a sexually dimorphic regulatory node of energy expenditure

Estrogen signaling in the central nervous system promotes weight loss by increasing thermogenesis and physical activity in the ventromedial hypothalamus (VMH), but the precise neuronal populations regulating these aspects of energy expenditure remain unclear. Here we define the molecular and functional heterogeneity of the VMH using single cell RNA sequencing, in situ hybridization, chemogenetic activation, and targeted gene knockdown. We describe six molecularly distinct neuron clusters in the VMH. In females, estrogen receptor alpha (ER) is restricted to neurons expressing tachykinin-1 (Tac1) or reprimo (Rprm). Further, Tac1 and Rprm expression is enriched in females, a sex difference that is established by permanent effects of gonadal hormones early in life. Finally, while Tac1 ablation selectively impairs movement, here we show that silencing Rprm selectively dysregulates temperature without affecting physical activity. Together this work provides a novel architectural framework whereby distinct and sexually differentiated neuron populations within the VMH mediate sex-specific aspects of metabolic homeostasis.

neuroscience↗