Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

Abstract

SUMMARY The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may therefore be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss, and hence to prevent weight regain.

Determination of neurotensin projections to the ventral tegmental area in mice

“…Studies across species were limited by the inability to easily identify Nts-expressing cells, but the recent development of Nts Cre mice enables the facile detection and manipulation of mouse Nts neurons using Cre-Lox technology. Using these mice we have identified a large population of Nts neurons in the LHA that project to the VTA, consistent with the prior afferent mapping done in rats, and manipulation of these LHA Nts neurons reveals their crucial contributions to motivated behavior and energy balance (Brown et al, 2017; Leinninger et al, 2011; Opland et al, 2013; Patterson et al, 2015; Woodworth et al, 2017b). The LHA may be just one of several sites by which Nts orchestrates distinct behavioral responses in the mouse VTA, thus it will be important to define all Nts afferents to the VTA and test their roles individually.…”

“…To our knowledge this is the first comprehensive definition of mouse Nts afferents to the VTA, and is a first step toward understanding how Nts coordinates a diverse repertoire of behaviors in mice. Indeed, since Nts afferents from the MPO and LHA of mice modify DA-mediated social interaction and energy balance, respectively (McHenry et al, 2017; Patterson et al, 2015; Woodworth et al, 2017b) it is possible that each Nts circuit orchestrates a specific motivated behavior via the VTA. Going forward it will be important to determine the particular roles of each Nts projection, and hence precise mechanisms to influence feeding, locomotor activity, social behavior, sleep, and response to addictive drugs.…”

“…These POA Nts neurons did not, however, modulate rewarding feeding behavior. By contrast, experimental activation of LHA Nts neurons, at least some of which project to the VTA, suppressed motivated feeding while promoting drinking and locomotor activity, which led to weight loss (Woodworth et al, 2017b). LHA Nts-mediated feeding suppression and DA release to the NA was dependent on signaling via Nts receptor-1, thus, Nts released from LHA Nts neurons likely acts directly via the subset of VTA neurons that co-express Nts receptor-1 and DA (Woodworth et al, 2017a, b).…”

“…By contrast, experimental activation of LHA Nts neurons, at least some of which project to the VTA, suppressed motivated feeding while promoting drinking and locomotor activity, which led to weight loss (Woodworth et al, 2017b). LHA Nts-mediated feeding suppression and DA release to the NA was dependent on signaling via Nts receptor-1, thus, Nts released from LHA Nts neurons likely acts directly via the subset of VTA neurons that co-express Nts receptor-1 and DA (Woodworth et al, 2017a, b). It has yet to be determined whether POA Nts neurons that project to the VTA mediate behavior via release of Nts and regulation of Nts receptor-1 expressing DA neurons or via the many Nts receptor-2 expressing glia in this region (Woodworth et al, 2017a).…”

Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

“…Since the LHA receives afferents from the medial preoptic area (MPO) and subfornical organ, two brain areas that relay changes in blood osmolality to other regions of the brain [86], it is tempting to speculate that LHA Nts neurons might coordinate sensation of osmotic need with Nts-mediated drinking behavior. Indeed, experimental activation of LHA Nts neurons promotes voracious water intake [87]. Nts has also been shown to amplify the effect of hypertonic saline solution on the firing rate and depolarization of supraoptic magnocellular neurosecretory cells, which act as osmosensors and respond to hyperosmotic extracellular fluid by permitting vasopressin release from the neurohypophysis [88].…”