Chronic administration of brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reverses obesity induced by high-fat diet

Abstract

An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic paraventricular nucleus (PVN) reduces body weight by decreasing feeding and increasing energy expenditure (EE), in animals on standard laboratory chow. Animals have divergent responses to a high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested two hypotheses: 1) BDNF in the PVN reverses HFD-induced obesity, and 2) animals with higher body fat have a greater physiological response to BDNF than those with less body fat. Eighty-four 10-wk old rats were allowed HFD ad libitum for 9 wk and then prepared with bilateral PVN cannulas. Animals were then divided into tertiles based on their body fat rank: high, intermediate, and low (H, I, and L). Each group was further divided into 2 subgroups and then PVN injected with BDNF or control (artificial cerebrospinal fluid, aCSF) every other day for 3 wk. Energy intake (EI), body weight, and body composition were measured. At study's end, rats were killed to allow measurement of other metabolic indices. In parallel, another 12 rats were fed control diet (CD), PVN-cannulated and injected with aCSF. HFD exposure induced obesity, particularly in the H body fat group, with a significant increase in EI, body weight, fat mass, liver size, and serum glucose, triglycerides, insulin, and leptin. BDNF significantly reduced EI, body weight, body fat, lean mass, and serum metabolic indices. These BDNF effects were greatest in the H body fat group. These data indicate that BDNF reduced HFD-induced obesity and metabolic syndrome-like measures, and the animals with the most body fat had the most significant response to BDNF.

Fig. 1.

Flow chart of the study design, as described in the methods section. aCSF, artificial cerebrospinal fluid; BDNF, brain-derived neurotrophic factor; Exp, experiment.

Fig. 2.

Comparisons between animals fed the high-fat diet (HFD) and animals fed the control diet (CD) for 11 wk. A: HFD group had a significant increase in body weight after about 4-wk of the HFD compared with the CD rats, with more than 10% of that in the CD rats (inset). B: HFD group increased their body fat from day 4 and had significantly more relative body fat (body fat/body weight × 100%, inset) than the CD rats. *P < 0.05.

Fig. 3.

Time course of energy intake during BDNF intervention. The energy intake in the animals treated with BDNF in H (clear blue square), I (clear brown triangle), and L (clear maroon diamond) subgroups was significantly reduced compared with the corresponding aCSF-treated subgroups (corresponding solid color symbols). The H-BDNF rats had the lowest levels of energy intake and also consumed the smallest percentage of its corresponding aCSF-treated group when compared with the other subgroups (inset). The energy intake in the CD-C rats (solid green square) was lower than the rats treated with aCSF in the H, I, and L subgroups (P = 0.0756 for main effect). H, high body fat group; I, intermediate body fat group; L, low body fat group; HC, H subgroup treated with aCSF; H-BDNF, H subgroup treated with BDNF; IC, I subgroup treated with aCSF; I-BDNF, I subgroup treated with BDNF; LC, L subgroup treated with aCSF; L-BDNF, L subgroup treated with BDNF; CD, control diet; CD-C, CD group treated with aCSF. *P < 0.05, comparison between BDNF and aCSF treatment in H (blue), I (brown), and L (maroon) group.

Fig. 4.

Body weight during BDNF intervention. In the time course (A), body weight in the animals treated with BDNF in H (clear blue square), I (clear brown triangle), and L (clear maroon diamond) subgroups was significantly reduced compared with the corresponding aCSF-treated subgroups (corresponding solid color symbols). H-BDNF rats showed the greatest body weight reduction (B), the lowest percentage of the body weight of the aCSF-treated animals (C), and the lowest percentage of their own pretreatment weight (D). The body weight change in animals from the CD-C group (green solid square; A, B, D) was significantly lower than LC and comparable with HC and IC. H: high body fat group; I: intermediate body fat group; L: low body fat group; HC: H subgroup treated with aCSF; H-BDNF: H subgroup treated with BDNF; IC: I subgroup treated with aCSF; I-BDNF: I subgroup treated with BDNF; LC: L subgroup treated with aCSF; L-BDNF: L subgroup treated with BDNF; CD: control diet; CD-C: CD group treated with aCSF. *P < 0.05, comparison between BDNF and aCSF treatment in H (blue), I (brown) and L (maroon) group. #P < 0.05, comparison between CD-C and LC.

Fig. 5.

Body fat during BDNF intervention. In the time course (A), body fat in the animals treated with BDNF in H (clear blue square), I (clear brown triangle), and L (clear maroon diamond) subgroups was significantly reduced compared with the corresponding aCSF-treated subgroups (corresponding solid color symbols). The H-BDNF rats showed the significant reduction of body fat reduction (B) compared with I- and L-BDNF rats. The body fat in the BDNF-treated rats is displayed as a percentage of that in the aCSF-treated animals (C) and the percentage of their own pretreatment level (D). The body fat change in the animals from CD-C group (green solid square) is displayed in A, B, and D. Same groups studied as in Fig. 4. *P < 0.05, comparison between BDNF and aCSF treatment in H (blue), I (brown), and L (maroon) group. #P < Benjamini-Hochberg critical value P (comparison between H-BDNF and I-BDNF or L-BDNF).

Fig. 6.

Association between initial body fat and amount of body fat loss in BDNF-treated and HFD-fed rats. n = 27.

Fig. 7.

Histology of liver from CD-C, HC, and H-BDNF. aCSF/BDNF was injected in the PVN every other day for 22 days. At the end of experiment, the liver from CD-C, HC, and H-BDNF was harvested, cryostat sectioned, fixed with 10% formalin, and stained with H&E (A: for CD-C, B: for HC, and C: for H-BDNF) and Red Oil O (D: for HC and E: for H-BDNF). Representative example of each group is shown. Magnification is ×20. The scale bar represents 50 μM.