Interoceptive “satiety” signals produced by leptin and CCK

Abstract

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1 hr) level of food deprivation. Rats were trained with cues arising from1-hr and 24-hr food deprivation as discriminative stimuli. For one group, 24-hr food deprivation predicted the delivery of sucrose pellets, whereas 1-hr food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-hr food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 μg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 μg, i3vt) combined with CCK-8 (2 μg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1-than 24-hr food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5 mg/kg). Although neither dose suppressed intake, the 0.3 mg/kg dose produced interoceptive cues like 1-hr food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4mg/kg ,i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to "satiety".

Western-style diet impairs stimulus control by food deprivation state cues: Implications for obesogenic environments

“…First, research in our laboratory has shown that rats can use the interoceptive stimulus consequences of different levels of food deprivation as discriminative cues for the delivery of either mild shock (e.g., Davidson, 1987) or sucrose pellets (e.g., Davidson et al, 2005). Evidence for this learning has been obtained after as few as three reinforced trials (Davidson, Flynn, & Jarrard, 1992), and discriminative control generalizes from cues produced by food deprivation and satiation to hormonal manipulations that are known to promote or suppress feeding behavior (e.g., exogenous administration of ghrelin (Davidson et al, 2005) or CCK and leptin (Kanoski, Walls, Davidson, 2007), respectively). These latter findings confirm that interoceptive cues arising from hunger and satiety, rather than exteroceptive stimuli produced by features of the deprivation regimen, were the basis of discriminative responding.…”

“…These same rats are not impaired in learning simple discriminations and other learning and memory problems that are hippocampal-independent (Davidson et al, 2012; Hargrave et al, in this issue; Kanoski, Zhang, Zheng, & Davidson, 2010; Molteni, Barnard, Ying, Roberts, & Gomez-Pinilla, 2002). Rats maintained on these diets also exhibit signs of brain pathologies such as increased blood-brain barrier permeability, elevated markers of hippocampal inflammation, and reduced levels of brain neurotrophic factors (Grayson et al, 2013; Hsu & Kanoski, 2014; Kanoski, Walls, Davidson, Kanoski, & Walls, 2007; Miller & Spencer, 2014; Molteni et al, 2002; Sobesky et al, 2014). Moreover, some pathological symptoms have been observed most prominently in rats that also showed both heightened sensitivity to the obesity promoting effects of these diets and impaired hippocampal-dependent learning and memory performance (Davidson et al, 2012, 2013).…”

A potential role for the hippocampus in energy intake and body weight regulation

“…In addition, ghrelin has been identified as a gastric peptide that functions as a physiological meal initiation or "hunger" cue [4] that is elicited not only as a result of a change in an animal's nutrient status but also as a learned anticipatory response to environmental cues associated with food [5]. Peripherally administered CCK and leptin appear to have interoceptive sensory consequences similar to those produced by a low level (e.g., 1 hr) of food deprivation [6], whereas the cue properties of peripherally or centrally administered ghrelin are similar to higher (e.g., 23-hr) levels of food deprivation [7,8]. All of these signals are transmitted to the brain where they are thought to be detected primarily by hypothalamic and hindbrain nuclei [2,9].…”

Plumbagin Inhibits Leptin-Induced Proliferation of Hepatic Stellate Cells via JAK2-STAT3 Pathway to Protect against Hepatic Fibrosis

“…Recently, some experiments and clinical studies have shown that leptin is closely related to liver fibrosis Leptin has characteristics of some cytokines when exerting biological effects, and its biological effects require its binding to leptin receptor (OB-R). OB-R is a member of the class I cytokine receptor family, and is composed of a single subunit containing extracellular domain, transmembrane domain and intracellular domain [10,11]. OB-R contains a long chain and a short chain, and its biological effects are attributed to the activation of the long chain.…”