Endocrinol Metab.  2017 Dec;32(4):475-484. 10.3803/EnM.2017.32.4.475.

Rebound Feeding in the Wake of Short-Term Suspension of Food Intake Differs in the Presence of Estrous Cycle Peak versus Nadir Levels of Estradiol

Affiliations
  • 1Department of Basic Pharmaceutical Sciences, School of Pharmacy, College of Health and Pharmaceutical Sciences, The University of Louisiana Monroe, Monroe, LA, USA. briski@ulm.edu

Abstract

BACKGROUND
Short-term interruption of feeding is ordinary in modern life but negatively impacts appetite control and body weight. Estradiol (E) imposes long-term inhibitory tonus on food consumption; however, E influence on energy repletion secondary to food deprivation (FD) is unclear. This study investigated the hypothesis that E signal strength regulates hyperphagic responses to FD of varying duration.
METHODS
Ovariectomized female rats were implanted with E-containing silastic capsules (30 [E-30] or 300 µg [E-300]/mL) to replicate plasma concentrations at cycle nadir versus peak levels.
RESULTS
Data show that food intake was increased equally in E-30 and E-300 rats after 12 hours of food deprivation (FD-12); yet, FD of 18 hours (FD-18) amplified refeeding by E-300 versus E-30. Caudal fourth ventricular administration of the 5"²-monophosphate-activated protein kinase (AMPK) inhibitor compound C (Cc) did not modify FD-induced hyperphagia in E-30 (regardless of FD interval) or E-300 animals exposed to FD-12, but diminished refeeding after FD-18 in E-300 rats. Cc-reversible hyperglycemia occurred in refed FD-18 groups. Serum insulin was resistant to FD-12 plus refeeding, but was elevated by AMPK-dependent mechanisms in refed E-300 FD-18 rats; equivalent Cc-insensitive decrements in circulating leptin occurred in all FD groups.
CONCLUSION
Current results show that estrous cycle peak, but not baseline, E levels engage hindbrain AMPK signaling to intensify hyperphagia in response to prolongation of FD. Observations of hindbrain AMPK-dependent hyperglycemia, alongside elevated insulin secretion, in refed rats exposed to FD-18 implicate this sensor in insulin resistance mechanisms of glucose partitioning in response to this metabolic imbalance.

Keyword

Refeeding; Food deprivation; AMP-activated protein kinases; Compound C; Estradiol; Insulin

MeSH Terms

AMP-Activated Protein Kinases
Animals
Appetite
Body Weight
Capsules
Eating*
Estradiol*
Estrous Cycle*
Female
Food Deprivation
Glucose
Humans
Hyperglycemia
Hyperphagia
Insulin
Insulin Resistance
Leptin
Plasma
Protein Kinases
Rats
Rhombencephalon
AMP-Activated Protein Kinases
Capsules
Estradiol
Glucose
Insulin
Leptin
Protein Kinases

Figure

  • Fig. 1 Effects of caudal fourth ventricular (CV4) administration of the adenosine 5′-monophosphate-activated protein kinase inhibitor compound C (Cc) on refeeding by estradiol (E)-treated ovariectomized (OVX) female rats after variable-length food deprivation (FD). Animals were exposed to FD (food was withdrawn at 9:00 PM) over a period of 12 (FD-12) or 18 (FD-18) hours, then injected into the CV4 with the vehicle (V; horizontal bars) or Cc (5.0 µg/2.0 µL DMSO; cross-hatched bars) prior to assessment of rebound feeding over a one hour period. Full-fed (FF; open bars) were treated by intra-CV4 V injection. Bars on the left side of the graph depict mean weight of consumed food±standard error of the mean after FD-12 by groups of 30 (E-30) or 300 (E-300) µg E/mL-implanted OVX rats treated by FF/V, FD/V, or FD/Cc (n=6 rats/group). On the right-hand side of the graph, bars show mean intake±SEM after FD-18 by groups of 30 (E-30) or 300 (E-300) µg E/mL-implanted OVX rats treated by FF/V, FD/V, or FD/Cc (n=6 rats/group). aP<0.05 vs. FF; bP<0.05 vs. FD+V; cP

  • Fig. 2 Effects of compound C (Cc) on glycemic responses to refeeding by groups of 30 (E-30) or 300 (E-300) rats. Animals were exposed to 12 hours of food deprivation (FD-12; left side of graph) or 18 hours of food deprivation (FD-18; right side of graph) were injected into the caudal fourth ventricular (CV4) with vehicle (V; horizontal bars) or Cc (cross-hatched bars) before analysis of blood glucose at the conclusion of a 1 hour refeeding period. Full-fed (FF; open bars) were injected into the CV4 with V. On the left, bars show mean circulating glucose levels±standard error of the mean after refeeding by FF-12/V, FD-12/V, or FD-12/Cc groups of E-30 or E-300 rats (n=6 rats/group). Bars on the right illustrate mean blood glucose values±SEM after refeeding by groups of FF-18/V, FD-18/V, or FD-18/Cc E-30 or E-300 rats (n=6 rats/group). aP<0.05 vs. FF; bP<0.05 vs. FD+V.

  • Fig. 3 Effects of compound C (Cc) on serum leptin concentrations in refed groups of 30 (E-30) or 300 (E-300) rats. Bars depict mean serum leptin levels±SEM 1 hour after refeeding in the following groups: left-hand side of graph: full-fed (FF)-12/vehicle (V; open bars), 12 hours of food deprivation (FD-12)/V (horizontal bars), or FD-12/Cc (cross-hatched bars) groups of E-30 or E-300 rats (n=6 rats/group); and right-hand side of graph: FF-18/V (open bars), 18 hours of food deprivation (FD-18)/V (horizontal bars), or FD-18/Cc (cross-hatched bars) E-30 or E-300 rats (n=6 rats/group). aP<0.05 vs. FF.

  • Fig. 4 Effects of compound C (Cc) on serum insulin levels in refed groups of 30 (E-30) or 300 (E-300) rats. Bars depict mean serum insulin concentrations levels±SEM 1 hour after refeeding in the following groups: left-hand side of graph: full-fed (FF)-12/vehicle (V), 12 hours of food deprivation (FD-12)/V, or FD-12/Cc groups of E-30 or E-300 rats (n=6 rats/group); and right-hand side of graph: FF-18/V, 18 hours of food deprivation (FD-18)/V, or FD-18/Cc groups of E-30 or E-300 rats (n=6 rats/group). aP<0.05 vs. FF; bP<0.05 vs. FD+V.

  • Fig. 5 Effects of caudal fourth ventricular compound C (Cc) administration on hindbrain A2 nerve cell 5′-monophosphate-activated protein kinase (AMPK), phosphorylated AMPK (pAMPK), and dopamine-β-hydroxylase (DβH) protein responses to 12 hours of food deprivation (FD-12) or 18 hours (FD-18) in groups of 30 (E-30) or 300 (E-300) rats. (A) It depicts representative immunoblots of A2 AMPK (row A), pAMPK (row B), DβH (row C), and α-tubulin (row D). (B, C, D) These respectively illustrate mean optical density (O.D.) measures±SEM for A2 AMPK, pAMPK, and DβH protein profiles in groups of E-30 and E-300 animals exposed to FD-12 (left side of each graph) or FD-18 (right side of each graph) with or without Cc treatment. FF, full-fed; V, vehicle. aP<0.05 vs. FD-V.


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