The Dorsal Raphe Nucleus and the Integrative Control of Feeding: A Report on Research Supported by Pathway to Stop Diabetes

Abstract

Obesity is a major risk factor for the development of type 2 diabetes (T2D). While the connection between these two disease entities is still incompletely understood, even modest weight loss can greatly reduce the risk of developing T2D and its sequelae. With the recent success of antiobesity pharmacotherapies, which appear to exert their effects largely through the brainstem, there has been a resurgent interest in understanding the neural mechanisms governing food intake and body weight. Over the past decade or so, my laboratory has sought to understand the neural control mechanism underlying energy homeostasis, through the lens of a small region in the brainstem, known as the dorsal raphe nucleus (DRN). The DRN is a molecularly heterogeneous structure in the dorsal midbrain, which we have found contains multiple cell types that are capable of regulating food intake and energy expenditure, and consequently, body weight. Here, I detail progress made by our laboratory and others over the past decade in our understanding of the DRN at the molecular, cellular, and circuit levels, with a particular emphasis on the integrative regulation of feeding. This line of research has established the DRN as an important regulator of energy balance and opens up exciting new lines of inquiry into the neural control mechanism governing food intake and body weight. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. ARTICLE HIGHLIGHTS The dorsal raphe nucleus (DRN) is a key regulator of food intake and body weight. The DRN has historically been associated with feeding, as it houses the single largest population of serotonergic neurons in the mammalian brain. Few studies have demonstrated a direct role for DRN serotonergic neurons in regulating feeding; none of these studies have demonstrated effects near those elicited by serotonin, itself. There are many nonserotonergic cell types in the DRN that play an integral role in feeding. These DRN cell types play important roles in both hunger and satiation.