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Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus.

Luchtman DW, Chee MJ, Doslikova B, Marks DL, Baracos VE, Colmers WF - PLoS ONE (2015)

Bottom Line: Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED.The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density.These properties are consistent with a mechanism of body weight setpoint.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks' refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.

No MeSH data available.


Related in: MedlinePlus

HED refeeding restores MTII effects in outbred DIO-D Sprague Dawley rats.Four weeks of HED refeeding (subsequent to ≥ 3 week chow challenge) restored NS neuron IPSC sensitivity to 10 nM MTII in DIO-D rats without affecting MTII responses in DR rats. Numbers of neurons studied are as indicated in each column. * p < 0.05; ** p < 0.01.
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pone.0139462.g007: HED refeeding restores MTII effects in outbred DIO-D Sprague Dawley rats.Four weeks of HED refeeding (subsequent to ≥ 3 week chow challenge) restored NS neuron IPSC sensitivity to 10 nM MTII in DIO-D rats without affecting MTII responses in DR rats. Numbers of neurons studied are as indicated in each column. * p < 0.05; ** p < 0.01.

Mentions: Our results indicated an attenuated anorexigenic drive in rats that defend a higher body weight setpoint even after cessation of HED feeding. To determine whether the loss of melanocortin sensitivity in the PVN of DIO-D animals is irreversible, we returned a subset of DR and DIO-D rats to the HED and determined if returning DIO-D animals to ad libitum HED would restore MTII responses in PVN. After 3–4 weeks of ad libitum HED-refeeding, IPSCs in NS neurons from DIO-D rats were more sensitive to MTII (DIO-Drefed: +45.3 ± 8.5%, n = 9) than were those from age-matched DIO-D rats that remained on chow (DIO-D: +21.2 ± 5.2%, n = 9, p < 0.05; Fig 7). As a result, there were no longer any differences in MTII responses between DIO-Drefed rats and either age-matched HED-N rats or DRrefed rats (Fig 7). Therefore, although the DIO-D animals defend their body weight around a higher setpoint, presynaptic melanocortin responses in the PVN appear to retain their plasticity in response to changes in dietary energy density.


Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus.

Luchtman DW, Chee MJ, Doslikova B, Marks DL, Baracos VE, Colmers WF - PLoS ONE (2015)

HED refeeding restores MTII effects in outbred DIO-D Sprague Dawley rats.Four weeks of HED refeeding (subsequent to ≥ 3 week chow challenge) restored NS neuron IPSC sensitivity to 10 nM MTII in DIO-D rats without affecting MTII responses in DR rats. Numbers of neurons studied are as indicated in each column. * p < 0.05; ** p < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596859&req=5

pone.0139462.g007: HED refeeding restores MTII effects in outbred DIO-D Sprague Dawley rats.Four weeks of HED refeeding (subsequent to ≥ 3 week chow challenge) restored NS neuron IPSC sensitivity to 10 nM MTII in DIO-D rats without affecting MTII responses in DR rats. Numbers of neurons studied are as indicated in each column. * p < 0.05; ** p < 0.01.
Mentions: Our results indicated an attenuated anorexigenic drive in rats that defend a higher body weight setpoint even after cessation of HED feeding. To determine whether the loss of melanocortin sensitivity in the PVN of DIO-D animals is irreversible, we returned a subset of DR and DIO-D rats to the HED and determined if returning DIO-D animals to ad libitum HED would restore MTII responses in PVN. After 3–4 weeks of ad libitum HED-refeeding, IPSCs in NS neurons from DIO-D rats were more sensitive to MTII (DIO-Drefed: +45.3 ± 8.5%, n = 9) than were those from age-matched DIO-D rats that remained on chow (DIO-D: +21.2 ± 5.2%, n = 9, p < 0.05; Fig 7). As a result, there were no longer any differences in MTII responses between DIO-Drefed rats and either age-matched HED-N rats or DRrefed rats (Fig 7). Therefore, although the DIO-D animals defend their body weight around a higher setpoint, presynaptic melanocortin responses in the PVN appear to retain their plasticity in response to changes in dietary energy density.

Bottom Line: Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED.The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density.These properties are consistent with a mechanism of body weight setpoint.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks' refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.

No MeSH data available.


Related in: MedlinePlus