Endogenous VMH Amylin Signaling is Required for Full Leptin Signaling and Protection from Diet-induced Obesity

Overview

Journal Am J Physiol Regul Integr Comp Physiol

Publisher American Physiological Society

Specialty Physiology

Date 2015 Dec 18

PMID 26676252

Citations 18

Authors

Ambrose A Dunn-Meynell

Christelle Le Foll

Miranda D Johnson

Thomas A Lutz

Matthew R Hayes

Barry E Levin

Affiliations

Soon will be listed here.

Abstract

Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO (125)I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80-90% in 4-wk-old male DR rats reduced their ARC and VMN (125)I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.

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References

Baisley S, Baldo B . Amylin receptor signaling in the nucleus accumbens negatively modulates μ-opioid-driven feeding. Neuropsychopharmacology. 2014; 39(13):3009-17. PMC: 4229571. DOI: 10.1038/npp.2014.153. View

Hay D, Christopoulos G, Christopoulos A, Sexton P . Amylin receptors: molecular composition and pharmacology. Biochem Soc Trans. 2004; 32(Pt 5):865-7. DOI: 10.1042/BST0320865. View

Potes C, Lutz T . Brainstem mechanisms of amylin-induced anorexia. Physiol Behav. 2010; 100(5):511-8. DOI: 10.1016/j.physbeh.2010.03.001. View

Chance W, Balasubramaniam A, Chen X, Fischer J . Tests of adipsia and conditioned taste aversion following the intrahypothalamic injection of amylin. Peptides. 1992; 13(5):961-4. DOI: 10.1016/0196-9781(92)90057-a. View

Ravussin E, Smith S, Mitchell J, Shringarpure R, Shan K, Maier H . Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring). 2009; 17(9):1736-43. PMC: 2754219. DOI: 10.1038/oby.2009.184. View

Irani B, Le Foll C, Dunn-Meynell A, Levin B . Ventromedial nucleus neurons are less sensitive to leptin excitation in rats bred to develop diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2009; 296(3):R521-7. PMC: 2665853. DOI: 10.1152/ajpregu.90842.2008. View

Roth J, Hughes H, Coffey T, Maier H, Trevaskis J, Anderson C . Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat-fed female rats. Am J Physiol Endocrinol Metab. 2007; 293(4):E1112-7. DOI: 10.1152/ajpendo.00395.2007. View

Levin B, Dunn-Meynell A . Reduced central leptin sensitivity in rats with diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2002; 283(4):R941-8. DOI: 10.1152/ajpregu.00245.2002. View

Rahmouni K, Haynes W, Mark A . Cardiovascular and sympathetic effects of leptin. Curr Hypertens Rep. 2002; 4(2):119-25. DOI: 10.1007/s11906-002-0036-z. View

10.

Kusakabe T, Ebihara K, Sakai T, Miyamoto L, Aotani D, Yamamoto Y . Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice. Am J Physiol Endocrinol Metab. 2012; 302(8):E924-31. DOI: 10.1152/ajpendo.00198.2011. View

11.

Lutz T, Mollet A, Rushing P, Riediger T, Scharrer E . The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats. Int J Obes Relat Metab Disord. 2001; 25(7):1005-11. DOI: 10.1038/sj.ijo.0801664. View

12.

Chance W, Balasubramaniam A, Zhang F, Wimalawansa S, Fischer J . Anorexia following the intrahypothalamic administration of amylin. Brain Res. 1991; 539(2):352-4. DOI: 10.1016/0006-8993(91)91644-g. View

13.

Turek V, Trevaskis J, Levin B, Dunn-Meynell A, Irani B, Gu G . Mechanisms of amylin/leptin synergy in rodent models. Endocrinology. 2009; 151(1):143-52. DOI: 10.1210/en.2009-0546. View

14.

Bouret S, Gorski J, Patterson C, Chen S, Levin B, Simerly R . Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 2008; 7(2):179-85. PMC: 2442478. DOI: 10.1016/j.cmet.2007.12.001. View

15.

Paxinos G, Chai S, Christopoulos G, Huang X, Toga A, Wang H . In vitro autoradiographic localization of calcitonin and amylin binding sites in monkey brain. J Chem Neuroanat. 2004; 27(4):217-36. DOI: 10.1016/j.jchemneu.2004.03.005. View

16.

Osaka T, Tsukamoto A, Koyama Y, Inoue S . Central and peripheral administration of amylin induces energy expenditure in anesthetized rats. Peptides. 2008; 29(6):1028-35. DOI: 10.1016/j.peptides.2008.02.002. View

17.

Becskei C, Riediger T, Zund D, Wookey P, Lutz T . Immunohistochemical mapping of calcitonin receptors in the adult rat brain. Brain Res. 2004; 1030(2):221-33. DOI: 10.1016/j.brainres.2004.10.012. View

18.

Trevaskis J, Coffey T, Cole R, Lei C, Wittmer C, Walsh B . Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms. Endocrinology. 2008; 149(11):5679-87. DOI: 10.1210/en.2008-0770. View

19.

Howard J, Cave B, Oksanen L, Tzameli I, Bjorbaek C, Flier J . Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med. 2004; 10(7):734-8. DOI: 10.1038/nm1072. View

20.

Bhavsar S, Watkins J, Young A . Synergy between amylin and cholecystokinin for inhibition of food intake in mice. Physiol Behav. 1998; 64(4):557-61. DOI: 10.1016/s0031-9384(98)00110-3. View