The Schwartz Laboratory

The Schwartz laboratory investigates the role of the brain in the control of both energy balance and glucose homeostasis with a focus on how defects in these systems contribute to the pathogenesis of obesity and diabetes. Our lab, in collaboration with the lab of Greg Morton, has shown that circulating hormones (such as leptin) can act in the brain to normalize elevated blood glucose levels in diabetic animals by powerfully activating insulin-independent processes. Specifically, our work centers on the concept that when the brain senses that body energy content and nutrient availability are in sufficient supply, further increases of stored energy (in the form of fat) and circulating nutrients (e.g., glucose) are resisted. Consequently, a decrease in neuronal input from one or more of these afferent signals alerts the brain to a current or pending deficiency of stored energy or nutrient availability. In turn, the brain activates responses that increase food intake, reduce energy expenditure, and raise circulating levels of glucose and other nutrients. Under normal circumstances, the resultant increase of body fat content and plasma levels of glucose, leptin, insulin, and free fatty acids are sensed in the brain, such that the adaptive response to nutritional deprivation is terminated upon the return of body fat mass and blood glucose levels to their original values. However, defects in the ability to mount, sense or respond to these humoral signals by neurocircuits in the mediobasal hypothalamus are proposed to be highly prevalent in human populations, and these defects collectively can set in motion a vicious cycle of weight gain, insulin resistance and impaired insulin secretion that can lead to type 2 diabetes.

In addition to our work investigating the central actions of leptin on energy balance and glucose metabolism over >2 decades, our lab focuses on the anti-diabetic effects of members of the FGF family, including FGF19, FGF21 and FGF1. In each case, the brain has emerged as a key target for these beneficial effects. Of particular interest is that in both rat and mouse models of T2D, a single injection of FGF1 into the brain induces diabetes remission that is sustained for weeks or months. We have subsequently localized this unprecedented effect to the mediobasal hypothalamus, and our current work investigates the hypothesis that defective glucose sensing in this brain area contributes to diabetes pathogenesis, and that this defect is ameliorated by the action of FGF1 in this brain area. Accordingly, ongoing studies aimed at delineating the cellular and molecular underpinnings of this effect have important implications at both a basic science and translational level. A key long-term goal is to translate these findings into novel approaches to the treatment of T2D.

Another area of active research pertains to perineuronal nets (PNNs), extracellular matrix (ECM) specializations that enmesh key neurons in a circuit and thereby regulate their function. We recently showed that neurons crucial for metabolic homeostasis located at the junction of the arcuate nucleus and median eminence (a mediobasal hypothalamic area specialized for sensing humoral signals) are enmeshed by PNNs. Our ongoing studies seek to determine the role played by these PNN-enmeshed neurons in how the brain senses glucose and other relevant humoral signals.