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. 2016 Feb;157(2):679-91.
doi: 10.1210/en.2015-1622. Epub 2015 Dec 14.

Intermittent Fasting Promotes Fat Loss With Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice

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Intermittent Fasting Promotes Fat Loss With Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice

Juliet D Gotthardt et al. Endocrinology. .
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Abstract

Clinical studies indicate alternate-day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into four groups and either maintained on ad libitum HFD, received alternate-day access to HFD (IMF-HFD), and switched to ad libitum low-fat diet (LFD; 10% fat) or received IMF of LFD (IMF-LFD). After 4 weeks, IMF-HFD (∼13%) and IMF-LFD (∼18%) had significantly lower body weights than the HFD. Body fat was also lower (∼40%-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (∼12%-13%) compared with the HFD and IMF-HFD groups. Oral glucose tolerance area under the curve was lower in the IMF-HFD (∼50%), whereas the insulin tolerance area under the curve was reduced in all diet interventions (∼22%-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (∼55%-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with the ad libitum-fed groups, whereas NE content was higher (∼19%-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (∼65%-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and neuropeptide Y, suggesting the counterregulatory processes of short-term weight loss are associated with an IMF dietary strategy.

Figures

Figure 1.
Figure 1.
Male mice were placed on a HFD (45% fat) to promote DIO. After 8 weeks, mice continued on the HFD (control group; n = 8), were placed on an alternate-day calorie deprivation IMF protocol with HFD (IMF-HFD; n = 8), switched to a control LFD (10% fat; n = 8), or placed on placed on IMF protocol with LFD (IMF-LFD; n = 8). Data are represented as means ± SEM. A, Body weights of mice at the end of 4 weeks of the diet intervention. B, Average cumulative food intake (kilocalories) over 4 weeks. *, Difference (P < .05) from HFD; ***, difference from HFD (P < .001).
Figure 2.
Figure 2.
Body composition as assessed by EchoMRI in all groups at the end of 4 weeks of the diet intervention. Data are represented as means ± SEM. A, Fat mass (grams). B, Lean body mass (grams). ***, Difference from HFD (P < .001); *, difference (P < .05) from HFD; $, difference (P < .05) from IMF-HFD.
Figure 3.
Figure 3.
RER measured by indirect calorimetry (24 h; fed day) in all groups at the end of 4 weeks of the diet intervention. Data are represented as means ± SEM. A, v.CO2. B, v.O2 C, RER. D, RER data as a function of body weight. *, Difference (P < .05) from HFD; **, difference (P < .01) from HFD; #, difference (P < .05) from LFD; ###, difference (P < .001) from LFD; $$$, difference (P < .001) from IMF-HFD.
Figure 4.
Figure 4.
OGTTs and insulin tolerance tests in all groups at the end of 4 weeks of the diet intervention. Data are represented as means ± SEM. A, Blood glucose (milligrams per deciliter) response to an oral bolus of glucose (2 g/kg) over 180 minutes. Values for IMF-HFD and LFD overlap. B, AUC of the glucose tolerance test. C, Blood glucose response to an ip injection of insulin (0.75 U/kg) over 120 minutes. D, AUC of insulin tolerance test. *, Difference (P < .05) from HFD; **, difference (P < .01) from HFD; ***, difference (P < .001) from HFD; #, difference (P < .05) from LFD; ###, difference (P < .001) from LFD; ##, difference (P < .01) from LFD; $, difference (P < .05) from IMF-HFD; $$, difference (P < .01) from IMF-HFD; $$$, difference (P < .001) from IMF-HFD.
Figure 5.
Figure 5.
Terminal levels of plasma hormones in all groups at the end of 4 weeks of the diet intervention. Data are represented as means ± SEM. A, Insulin B, Leptin. C, Ghrelin. *, Difference (P < .05) from HFD; ***, difference (P < .001) from HFD.
Figure 6.
Figure 6.
Biogenic amines were measured by HPLC in the anterior and posterior medial hypothalamus in all groups at the end of 4 weeks of the diet intervention (n = 8 per group). A, NE. B, DA. C, 5-HT. D, 5HIAA. E, HVA. Data are represented as means ± SEM. *, Difference (P < .05) from HFD; #, difference (P < .05) from LFD; $, difference (P < .05) from IMF-HFD.

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