UCLA

Estrogen receptor α (ERα)-expressing neurons in the ventrolateral region of the ventromedial hypothalamus (VMHvl) mediate sex-specific aspects of energy balance. Elegant studies by Miguel L�pez and colleagues showed that central delivery of estradiol (E2) promotes increased energy expenditure, increased core body temperature, and induces the expression of thermogenic markers consistent with increased BAT thermogenesis. Conversely, loss-of-function studies by our group and others have shown that ablation of ERα or ERα-containing neurons in the VMH of female mice leads to a positive energy balance, marked by reduced locomotor activity, decreased thermogenic function of BAT, and a food intake-independent weight gain. Finally, epidemiologic data shows that women transitioning to menopause exhibit decreased energy expenditure and decreased fat oxidation compared to age-matched premenopausal women. Therefore, identifying the neuronal mediators of estrogenic regulation of energy balance in the VMH could begin to unravel the mechanisms that predispose post-menopausal women to obesity.

By way of single-cell RNA sequencing of murine VMH lineage neurons, we identified 6 distinct neuron clusters in the VMH. Using in situ hybridization, I found that 4 of these clusters, marked by differential expression of the neuropeptide (or neuropeptide-precursor)-encoding genes tachykinin 1 (Tac1), prodynorphin (Pdyn), and somatostatin (Sst), as well as the p53-induced gene reprimo (Rprm), identified distinct ERα+ neuron populations in the VMHvl. Furthermore, I determined that Tac1 and Rprm also identified female-biased, sexually differentiated neuron populations. Using in vivo stereotaxic targeting, I observed that siRNA-mediated knockdown of Rprm in the VMHvl leads to an increase in core body temperature in female but not male mice. Using thermographic image analysis I found that siRNA-mediated knockdown of Rprm in the VMHvl induces increased temperature of the interscapular BAT area indicative of enhanced thermogenesis. Finally, to determine the significance of Rprm neuron activity on energy balance independent of Rprm gene expression manipulation, I contributed to the development of a novel Rprm-Cre-FRT mouse model that will enable chemogenetic/optogenetic activation of Rprm neurons. Furthermore, this model will allow for long-term studies on the role of Rprm on body weight and energy expenditure regulation, as well as the interaction of Rprm with ERα signaling.

Together, my findings suggest that Rprm identifies a sexually differentiated VMH neuron population that contributes to the female-specific regulation of core body temperature and BAT thermogenesis attributed to E2 signaling in the VMH.