Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats

Abstract

Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentration and increased hypothalamic corticotropin-releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results indicate that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches.

Keywords: Adrenocorticotropic hormone; Roux-en-Y gastric bypass; corticosterone; corticotropin-releasing hormone; pair-feeding; vertical sleeve gastrectomy.

Figure 1

Metabolic parameters pre- and post-surgery. (A) Total, lean and fat mass of male rats fed either chow (n=12) or high-fat diet (HFD; n=43) for 7 weeks to induce obesity prior to surgical treatments. Student's t test, *p < 0.05. (B) Body weights of Lean (chow-fed) and HFD-fed Obese, vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) and Pair-fed (calorie-restricted) rats during the 30 days following surgical treatment. Two-way ANOVA with repeated measures followed by Bonferroni post-hoc test, *p<0.05 for Obese vs. all other groups. (C) Daily average caloric intake during the 30 days post-surgery. Two-way ANOVA with repeated measures followed by Bonferroni post-hoc test, *p<0.05 for both Obese and Lean vs. all other groups. (D) Daily average caloric intake normalized to body weight during the 30 days post-surgery. Two-way ANOVA with repeated measures followed by Bonferroni post-hoc test, *p<0.05 for both Obese and Lean vs. all other groups. n= 7–13/group for panels B–D. Data are presented as mean ±SEM.

Figure 2

Unstressed plasma corticosterone and adrenocorticotropic hormone (ACTH) concentrations in Lean (chow-fed) and high fat diet (HFD)-fed Obese, vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) and Pair-fed (calorie-restricted) rats. (A) Plasma corticosterone at 2 hours after lights-on (morning) and at 1 hour prior to lights-off (evening). Differing letters denote significant differences between treatment groups (p<0.05); two-way ANOVA with repeated measures followed by Bonferroni post-hoc test.(B) Plasma ACTH at corresponding times to those in (A). n = 8–13/group. Data are shown as mean ± SEM.

Figure 3

Acute post-stress plasma corticosterone and adrenocorticotropic hormone (ACTH) concentrations in Lean (chow-fed) and high fat diet (HFD)-fed Obese, vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) and Pair-fed (calorie-restricted) rats. (A) Plasma corticosterone response to a 15-minute novel environment test (gray region in graph). Two-way ANOVA with repeated measures followed by Bonferroni post-hoc test, *p<0.05 for RYGB vs. all other groups. (B) Area-under-the-curve (AUC) of the plasma corticosterone response shown in (A). One-way ANOVA followed by a Tukey post-hoc test: differing letters denote significant differences between treatment groups (p<0.05). (C) Corresponding plasma ACTH concentrations from the acute novel environment test in A. Two-way ANOVA with repeated measures followed by Bonferroni post-hoc test, *p<0.05 vs. Lean group, #p<0.05 for Pair-fed vs. Obese. (D) AUC of the plasma ACTH response shown in (C). One-way ANOVA followed by a Tukey post-hoc test: differing letters denote significant differences between treatment groups (p<0.05). n = 7–13/group. Data are presented as mean ±SEM.

Figure 4

Terminal organ weights of Lean (chow-fed) and high fat diet (HFD)-fed Obese, vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) and Pair-fed (calorie-restricted) rats at 60 days after surgical treatments. (A) Thymus weight, (B) Thymus weight normalized to body weight, (C) Total adrenal weight (sum of left and right adrenals), and (D) Total adrenal weight normalized to body weight. For all panels, differing letters denote statistically significant differences between treatment groups (p<0.05); one-way ANOVA followed by a Tukey post-hoc test. n = 7–13/group. Data are presented as mean ±SEM.

Figure 5

Hypothalamic mRNA expression in Lean (chow-fed) and high fat diet (HFD)-fed Obese, vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) and Pair-fed (calorie-restricted) rats at 27–29 days after surgical treatments. (A) Pro-opiomelanocortin (POMC), (B) Agouti-related peptide (AgRP), (C) Corticotropin-releasing hormone (CRH), (D) Arginine-vasopressin (AVP), (E) Glucocorticoid receptor (GR), and (F) Mineralocorticoid receptor (MR). For all panels, differing letters denote statistically significant differences between treatment groups (p<0.05); one-way ANOVA followed by a Tukey post-hoc test. Note that ANOVA identified an overall treatment effect for AgRP mRNA (p = 0.032), but no specific group differences were identified on subsequent post-hoc analysis. n = 7–8/group. Data are presented as mean ±SEM.