Gonadal steroid hormones are the principal drivers of sex-variable biology in vertebrates. In the brain, estrogen (17β-estradiol) establishes neural sex differences in many species and modulates mood, behavior, and energy balance in adulthood. To understand the diverse effects of estradiol on the brain, we profiled the genomic binding of estrogen receptor alpha (ERα), providing the first picture of the neural actions of any gonadal hormone receptor. To relate ERα target genes to brain sex differences we assessed gene expression and chromatin accessibility in the posterior bed nucleus of the stria terminalis (BNSTp), a sexually dimorphic node in limbic circuitry that underlies sex-differential social behaviors such as aggression and parenting. In adult animals we observe that levels of ERα are predictive of the extent of sex-variable gene expression, and that these sex differences are a dynamic readout of acute hormonal state. In neonates we find that transient ERα recruitment at birth leads to persistent chromatin opening and male-biased gene expression, demonstrating a true epigenetic mechanism for brain sexual differentiation. Collectively, our findings demonstrate that sex differences in gene expression in the brain are a readout of state-dependent hormone receptor actions, rather than other factors such as sex chromosomes. We anticipate that the ERα targets we have found will contribute to established sex differences in the incidence and etiology of neurological and psychiatric disorders.

The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.

Despite the profound effects of nutrition and physical activity on human health, our understanding of the molecules mediating the salutary effects of specific foods or activities remains remarkably limited. Here, we share our ongoing studies that use unbiased and high-resolution metabolomics technologies to uncover the molecules and molecular effectors of diet and exercise. We describe how exercise stimulates the production of Lac-Phe, a blood-borne signaling metabolite that suppresses feeding and obesity. Ablation of Lac-Phe biosynthesis in mice increases food intake and obesity after exercise. We also describe the discovery of an orphan metabolite, BHB-Phe. Ketosis-inducible BHB-Phe is a congener of exercise-inducible Lac-Phe, produced in CNDP2+ cells when levels of BHB are high, and functions to lower body weight and adiposity in ketosis. Our data uncover an unexpected and underappreciated signaling role for metabolic fuel derivatives in mediating the cardiometabolic benefits of diet and exercise. These data also suggest that diet and exercise may mediate their physiologic effects on energy balance via a common family of molecules and overlapping signaling pathways.