Neural Control of Energy Balance: Biochemistry behind Glucose Metabolism and Obesity

Recent insights into the neural circuits controlling energy balance and glucose homeostasis have rekindled the hope for development of novel treatments for obesity and diabetes. However, many therapies contribute relatively modest beneficial gains with accompanying side effects, and the mechanisms of action for other interventions remain undefined. This Review summarizes current knowledge linking the neural circuits regulating energy and glucose balance with current and potential pharmacotherapeutic and surgical interventions for the treatment of obesity and diabetes.

Obesity, diabetes, and associated disorders represent a major public health challenge for North America, Europe, and increasingly the rest of the world. Both obesity and diabetes inflict health and economic burdens that require coordinated strategies to both prevent and treat these disorders. Indeed, a major barrier in the management and prevention of obesity is that weight loss due to lifestyle changes alone is inherently difficult. For many, this means that dieting-induced weight loss initially results in tangible beneficial effects but is often followed by a return to previous energy intake and consequently a rebound weight gain.

Numerous neurobiological and physiological mechanisms that regulate energy balance exist. In particular, it has become increasingly evident that the brain plays an important role in sensing energy demands and storage in order to maintain/defend body weight within a rather tight range. Studies ranging from worms, flies, and mice to humans have identified key conserved genes and neural pathways that are critical in regulating energy balance and glucose homeostasis. Moreover, the identification of human mutations in these or analogous pathways has led to hope that it may be possible to develop rational strategies based on animal model studies that may ultimately lead to successful therapeutic intervention in humans. In this Review, we will highlight how advances in understanding the neurophysiology underlying metabolism, including an increased understanding of neural circuits, may hold promise for development of adjunct therapies in the treatment of obesity and associated co-morbidities, including diabetes. Several recent Reviews have provided more detailed information and review of the primary literature regarding the respective circuits and approaches highlighted here (Barsh et al., 2000; Cone, 2005; Deisseroth, 2012; Farooqi and O’Rahilly, 2005; Heisler et al., 2003; Myers and Olson, 2012; Powley et al., 2005; Schwartz and Porte, 2005; Wikberg and Mutulis, 2008).