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. 2022 Sep 1;323(3):E267-E280.
doi: 10.1152/ajpendo.00088.2022. Epub 2022 Jul 13.

Leptin receptor-expressing cells in the ventromedial nucleus of the hypothalamus contribute to enhanced CCK-induced satiety following central leptin injection

WonMo Ahn  1 , John Latremouille  1 , Ruth B S Harris  1
Affiliations

Leptin receptor-expressing cells in the ventromedial nucleus of the hypothalamus contribute to enhanced CCK-induced satiety following central leptin injection

WonMo Ahn et al. Am J Physiol Endocrinol Metab. .

Abstract

Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 µg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-µg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 µg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet.NEW & NOTEWORTHY Leptin is a feedback signal in the control of energy balance, whereas cholecystokinin (CCK) is a short-term satiety signal that inhibits meal size. The two hormones synergize to promote satiety. We tested whether leptin receptors in the ventromedial nucleus of the hypothalamus (VMH) contribute to the synergy. The results suggest that there is a requirement for a baseline level of activation of leptin receptors in the VMH in order for CCK to promote satiety.

Keywords: Sprague-Dawley rats; food intake; high-fat diet; meal size and duration.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
A: food intake during the 12-h intervals following injection of different doses of leptin into the ventromedial hypothalamus (VMH). B: weight change of the rats 12 and 36 h after the injections. Data are means ± SE for six male rats each of which was tested in each condition. Values for intake 12–24 h after injection that do not share a common superscript are significantly different determined by paired t test. C: one h food intake following an intraperitoneal injection of different doses of cholecystokinin (CCK). Data are means ± SE for 12 male rats each of which was tested in each condition. *Significant difference from saline injection determined by paired t test.
Figure 2.
Figure 2.
A: cumulative intake of rats that received ventromedial hypothalamus (VMH) injections of 50 ng leptin and/or peripheral injections of 1 µg/kg cholecystokinin (CCK). The location of a guide cannula (B), different parameters for the first meal consumed after the injections (C), and meal parameters for the second meal (D). Data are means ± SE for 12 male rats each of which was tested in the each of the four conditions. Values that do not share a common superscript within a panel are significantly different determined by analysis of variance of post hoc Tukey’s honestly significant difference test.
Figure 3.
Figure 3.
A: 30 min and 1 h cumulative intake of rats fed a low-fat (LF) diet and treated with ventromedial hypothalamus (VMH) leptin and/or peripheral cholecystokinin (CCK) in experiment 4. B: same data for rats fed high-fat (HF) diet. Data are means ± SE for seven male rats that were each tested in each condition. Values with a panel that do not share a common superscript are significantly different, determined by analysis of variance and post hoc Tukey’s honestly significant difference test.
Figure 4.
Figure 4.
A: 1 h energy intake of male rats in experiment 5 that were offered low-fat (LF) or high-fat (HF) diet and were injected intraperitoneally with increasing doses of cholecystokinin (CCK). Lep-Sap rats had received ventromedial hypothalamus (VMH) injections of leptin-conjugated saporin 30 days before they were offered the experimental diet and CCK testing started 11 days after the first day that each diet was offered. B: cumulative intake of the rats at 30 min, 1 and 2 h after injection with 1 µg/kg CCK. Data are means ± SE for six male rats that were each tested in each condition on each diet. Values with a panel that do not share a common superscript are significantly different, determined by analysis of variance and post hoc Tukey’s honestly significant difference test.
Figure 5.
Figure 5.
A: pSTAT3-IR in the medial arcuate (ArcM), lateral arcuate (ArcL), and dorsomedial ventromedial hypothalamus (VMHdm) of rats that had received VMH injections of Blank-Sap or Lep-Sap. Images on the right-hand side of the panel show typical levels of expression in a Blank-Sap and Lep-Sap rat. *Lep-Sap significantly depleted the VMHdm pSTAT3-Ir, but did not change that in the ArcM or ArcL. B: cumulative intake of chow for Blank-Sap rats for different time intervals after lateral ventricle injection of 2 µg of leptin and/or intraperitoneal injection of 1 µg/kg of cholecystokinin (CCK) in experiment 6. C: same cummulative intake data, but for rats that has been injected with Lep-Sap before the start of the experiment. Data are means for six male rats, each Lep-Sap rats and each Blank-Sap rat was tested with each dose of CCK. Values with a panel that do not share a common superscript are significantly different, determined by analysis of variance and post hoc Tukey’s honestly significant difference test.
Figure 6.
Figure 6.
A: average bout size for male rats in experiment 6 30 min and 1 h after injection. B: average meal size for different time intervals after lateral ventricle injection of 2 µg of leptin and/or intraperitoneal injection of 1 µg/kg cholecystokinin (CCK) in rats that had received ventromedial hypothalamus (VMH) injections of Blank-Sap or with Lep-Sap 30 days before the start of the experiment. C: weight change of rats 12 and 36 hours after central injection of 2 μg leptin or saline and peripheral injection of CCK or saline. Data are means ± SE for groups of eight Lep-Sap rats and six Blank-Sap male rats. Values with a panel that do not share a common superscript are significantly different, determined by analysis of variance and post hoc Tukey’s honestly significant difference test.
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