Sex differences in behavior and metabolism

Abstract

Men and women exhibit distinct illness patterns and disparate responses to pharmacotherapies. However, there is a scarcity of preclinical studies that systematically compare the sexes. The overarching aim of this thesis was to identify sex differences, and their underlying mechanisms, in metabolic and behavioral control within rodent models of obesity and anxiety. Specifically, we explored novel brain targets and mechanisms for the control of appetite, energy expenditure, and emotionality. In Paper I, we found that mice and rats subjected to diet-induced obesity responded with sexually divergent eating behavior and adaptations in energy expenditure. In Paper II, we showed that obesity reduced the expression of interleukin-6 (IL-6) in the brain of males only, and that the role of IL-6 in the parabrachial nucleus (PBN) is sexually dimorphic, such that it is only necessary for normal brown adipose tissue thermogenesis in males. In Paper III, we discovered that the locus coeruleus (LC) is a novel site for the behavioral effects of the hunger hormone ghrelin. We demonstrated that males have higher ghrelin receptor levels in the LC, and that there is a sex difference in response to ghrelin receptor activation and blockade, in regards to food motivation and anxiety-like behavior. Finally, in Paper IV, we investigated whether brain-produced estrogen plays a role in body weight regulation. We found a sexually dimorphic role of aromatase in the amygdala, such that it is only necessary for normal energy homeostasis and food motivation in females. Collectively, the work presented in this thesis underscores the significance of considering biological sex in the context of energy balance regulation and associated behaviors. These findings contribute to a broader conversation on addressing sex differences in human disease, with the ultimate goal of enhancing the success of drug development.