Leptin Signaling in the Medial Nucleus Tractus Solitarius Reduces Food Seeking and Willingness to Work for Food

Abstract

The adipose-derived hormone leptin signals in the medial nucleus tractus solitarius (mNTS) to suppress food intake, in part, by amplifying within-meal gastrointestinal (GI) satiation signals. Here we show that mNTS leptin receptor (LepRb) signaling also reduces appetitive and motivational aspects of feeding, and that these effects can depend on energy status. Using the lowest dose that significantly suppressed 3-h cumulative food intake, unilateral leptin (0.3 mg) administration to the mNTS (3 h before testing) reduced operant lever pressing for sucrose under increasing work demands (progressive ratio reinforcement schedule) regardless of whether animals were energy deplete (food restricted) or replete (ad libitum fed). However, in a separate test of food-motivated responding in which there was no opportunity to consume food (conditioned place preference (CPP) for an environment previously associated with a palatable food reward), mNTS leptin administration suppressed food-seeking behavior only in chronically food-restricted rats. On the other hand, mNTS LepRb signaling did not reduce CPP expression for morphine reinforcement regardless of energy status, suggesting that mNTS leptin signaling differentially influences motivated responding for food vs opioid reward. Overall results show that mNTS LepRb signaling reduces food intake and appetitive food-motivated responding independent of energy status in situations involving orosensory and postingestive contact with food, whereas food-seeking behavior independent of food consumption is only reduced by mNTS LepRb activation in a state of energy deficit. These findings reveal a novel appetitive role for LepRb signaling in the mNTS, a brain region traditionally linked with processing of meal-related GI satiation signals. Keywords: satiation; reward; conditioned place preference; obesity; hindbrain; NTS INTRODUCTIONLeptin, secreted primarily from white adipose cells, acts on receptors (leptin receptor, LepRb) in the brain to reduce body weight by suppressing food intake and increasing energy expenditure. Historically, attention has been directed toward leptin's action in the hypothalamus, particularly the arcuate hypothalamic nucleus (ARC). More recent findings reveal that leptin's powerful control over energy balance is anatomically distributed (Grill, 2010;Grill and Kaplan, 1990;Grill and Kaplan, 2002a) as it involves contributions from midbrain and forebrain regions such as the ventral tegmental area (Fulton et al, 2006;Hommel et al, 2006) and the hippocampus (Kanoski et al, 2011) that are associated with the control of motivational, learned, and rewarding aspects of food intake, as well as in extra-ARC hypothalamic nuclei (Leinninger et al, 2009;Zhang et al, 2011) and hindbrain nuclei (Grill et al, 2002b;Huo et al, 2007;Schwartz and Moran, 2002;Skibicka and Grill, 2009) whose neural processing is typically associated with the control of need-based food intake (ie, feeding driven by energy deficit). Within the hindbrain, the LepRb is most densely expressed in the me...

Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding

“…The current data lead to conclusions about mNTS receptor signaling and appetitive feeding behaviors that are similar to those of a recent study (20), in which mNTS leptin signaling reduced food-motivated behavior in PR and CPP paradigms. Collectively, these findings support a broader role for the mNTS in mediating food reward processing.…”

“…Experiment 2: effects of mNTS GLP-1 signaling on progressive ratio operant responding for sucrose pellets. Rats (n ϭ 10) maintained ad libitum on standard chow were habituated to 45-mg sucrose pellets (Bio-Serv; Frenchtown, NJ) in their home cages and were trained, as previously described (1,20) to press a lever to obtain pellets on a FR5 schedule of reinforcement (five lever presses required to receive one pellet). For all training sessions, the right lever was the active lever, and an inactive left lever served as a control for nonconditioned increases or decreases in operant responding.…”

“…Animals were returned to their home cages for the 3 h between injection and test session; food was withheld during this period. During the PR test, the effort required to obtain each pellet increased exponentially throughout the session, as previously described (1,20), using the formula:…”

“…Rats (n ϭ 17) maintained ad libitum on standard chow were trained for conditioned place preference (CPP), as previously described (20). All CPP training and testing sessions were performed in a dimly lit room.…”

Does Nutrient Sensing Determine How We “See” Food?

“…Part of this reason may be due to highly concentrated nutrients stimulating intestinal satiety signals and interfering with the stimulatory signals evoked by intestinal nutrients [84]. Thus, while appetition and satiation may share nutrient-sensing mechanisms, the signals are likely to be different as intestinal satiety signals do not generally condition preferences [99,100]. However, this has not been tested in knockout (KO) mice.…”