UCLA

Metabolism and reproduction are linked homeostatic processes. This linkage becomes particularly important for animals who gestate their young, as gestation and postpartum care are energetically taxing life stages. Indeed, long- and short-term measures of metabolic reserve and availability, adiposity and feeding, gate reproductive processes in mammals with ovaries. Many neuronal nodes and circuits that help mediate this tradeoff are located in the hypothalamus. As an important component of energy intake, feeding nodes have been investigated as responsive to reproductive cues such as gonadal hormones for many decades. Feeding is a complex behavior, tapping into both homeostatic and hedonic mechanisms. As such, there are many locations where metabolic and reproductive status may integrate and affect feeding behavior. This thesis explores how the tuberal nucleus (TN), a relatively new feeding node, may integrate metabolic and reproductive cues to affect food intake. Using the Cre-lox system and viral stereotaxic injections, somatostatin neurons in the TN (TNSST) were selectively manipulated to interrogate neuronal function. Chemogenetic activation of TNSST neurons increased food intake across sexes, but cell autonomous caspase ablation only decreased food intake in female mice (mice with ovaries) during the night of proestrus, when circulating hormones like estradiol are high. This apparent effect of estradiol was only evident in animals with a low body weight, and the inverse correlation of food intake and body weight during proestrus was completely eliminated with TNSST neuron ablation. Further analysis revealed that this body weight effect may be primarily determined by adiposity, as high levels of hypothalamic estradiol seem to increase communication between TNSST neurons and various adipocyte depots. This may be a direct effect of estradiol on TNSST neurons, as these neurons are both estrogen sensitive and responsive. Ongoing fat transplantation studies confirm the adipose dependency of this effect. Together, this dissertation proposes a model whereby TNSST neurons activate during periods of fertility to induce food intake when body reserves are low. Thus, sex differential recruitment and/or activation of TNSST neurons may work to mitigate the effects of sex steroids on behavioral feeding output. This dissertation research illustrates how gonadal steroid modulation of neuronal circuits can be context-dependent and gated by other physiological signals. Furthermore, this project illustrates how sex as a singular, coherent biological variable is insufficient for current explorations into the contributions of sexed physiologies to feeding behavior. Thus, this dissertation also proposes a framework shift to a “sex variables” paradigm that recognizes the limitations of binary, internally consistent sex in favor of a more contextual and expansive definition of sex and sexed physiologies.