Chronic exercise reduces hypothalamic transforming growth factor-β1 in middle-aged obese mice

Abstract

Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-β (TGF-β1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-β1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-β1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-β1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-β1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.

Keywords: TGFβ-1; aging; exercise; hypothalamus; obesity.

Figure 1. Effects of long-term of high-fat diet consumption in Middle-Age mice

Experimental design 1 (A). Body weight and epididymal fat (B and C) (n=5-8 per group). VO₂ (D), CO₂ (E), RER (F) (n= 4-5 per group). Ucp1 mRNA in the brown adipose tissue (n=5-8 per group) (G). The animals were fasted for 8 hours before the brown adipose tissue extraction. Data are expressed as means ± SEM. *, p<0.05 vs Young control group and ^&, p<0.05 vs Middle-Age fed on chow diet.

Figure 2. Effects of long-term of HFD on hypothalamic TGF-β1 accumulation and inflammatory genes in Middle-Age mice

Real time PCR assay of hypothalamic Tgf-β1 (A), Tnf-α, Il1-β, Tlr4, F4/80 (B) and Npy mRNA level (C) (n=4-7 per group). The animals were fasted for 8 hours before the hypothalamus extractions. Data are expressed as means ± SEM. *, p<0.05 vs Young control group and &, p<0.05 vs Middle-Age fed on chow diet.

Figure 3. Effects of chronic exercise in Middle-Aged obese mice

Experimental design 2 (A). Body weight change, cumulative food intake and average food intake (A-D) (n=10 per group). VO₂ (E), CO₂ (F) and ambulatory activity (G) (n= 4 per group). All analyses were made in the last day of training. Western blotting of UCP-1 protein level in BAT (H) and normalization of protein level by Tubulin (right) (I), picture of BAT, highlighting the coloration (J) (n= 6 per group). Data are expressed as means ± SEM. *, p<0.05 vs Sedentary group.

Figure 4. Effects of chronic exercise on hypothalamic TGF-β1 protein levels in Middle-Aged obese mice

Western blotting of IkB-α ser32 phosphorylation (A) and TGF-β1 protein level (C) and Protein level normalization with Tubulin (right) (B and D) (n= 8 per group). All analyses were made after the last day of training. Data are expressed as means ± SEM. *, p<0.05 vs Sedentary group.