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

Dirk W. Luchtman, Melissa J S Chee, Barbora Doslikova, Daniel Marks, Vickie E. Baracos, William F. Colmers

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0139462
JournalPLoS One
Volume10
Issue number10
DOIs
StatePublished - Oct 7 2015

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paraventricular hypothalamic nucleus
Melanocortins
low calorie diet
Paraventricular Hypothalamic Nucleus
Nutrition
Rats
high energy diet
Body Weight
Diet
body weight
obesity
rats
diet
neuropeptide Y
Obesity
refeeding
Neuropeptide Y
gamma-Aminobutyric Acid
neurons
energy density

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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, Dirk W.; Chee, Melissa J S; Doslikova, Barbora; Marks, Daniel; Baracos, Vickie E.; Colmers, William F.

In: PLoS One, Vol. 10, No. 10, e0139462, 07.10.2015.

Research output: Contribution to journalArticle

Luchtman, Dirk W. ; Chee, Melissa J S ; Doslikova, Barbora ; Marks, Daniel ; Baracos, Vickie E. ; Colmers, William F. / 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. In: PLoS One. 2015 ; Vol. 10, No. 10.
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