Neural control of energy balance: translating circuits to therapies

Abstract

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.

Figure 1. Integrated Model of the Central Melanocortin System and Connected Regions within the Nervous System Involved in Obesity and Diabetes

Recent discoveries highlight a circuitry within the brain that includes the hypothalamus as well as midbrain/hindbrain areas in the acute regulation of energy expenditure. This circuitry has also been demonstrated to have an overlapping role in the management of glucose homeostasis. Importantly, several neurotransmitters and peptides contribute to a distributed network of receptor systems within this circuit and provide potential substrates for non-surgical therapeutic intervention. Similarly, advancing technologies have raised potential surgical and non-surgical manipulation of cellular and nerve activity as a viable strategy in this circuit to combat obesity and diabetes. Abbreviations: NPY = neuropeptide Y; Pomc = pro-opiomelanocortin; AgRP = Agouti gene-related peptide; Arc = arcuate nucleus; GLP-1 = glucagon-like peptide 1.

Figure 2. Selected Therapeutic Options for Treating Obesity and Diabetes by Targeting the Brain

Current and promising therapeutics in the treatment of both obesity and diabetes have targeted neural connections including the melanocortin system, via pharmacological and/or device-assisted methods. Here we summarize a select number of targets (i.e., receptors and brain regions) that have been demonstrated to regulate at least in part effects of energy balance and glucose homeostasis. Abbreviations: hfDBS = high-frequency deep brain stimulation; VBLOC = vagal blocking; VNS = vagal nerve stimulation; Mc4r = melanocortin 4 receptor; DVC = dorsal vagal complex; PBN = parabrachial nucleus; tDCS = transcranial direct current stimulation; Arc = arcuate nucleus; VMH = ventrome-dial hypothalamic nucleus; LHA = lateral hypothalamic area; DMH = dorsal medial hypothalamic nucleus; PVH = paraventricular hypothalamus; DVC = dorsal vagal complex; IML = intermedio-lateral cell column; BAT = brown adipose tissue; WAT = white adipose tissue; DR = dorsal raphe nucleus.