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. 2020 Nov 13;10(11):462.
doi: 10.3390/metabo10110462.

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice

Santiago Guerra-Cantera  1   2   3 , Laura M Frago  1   2   3 , María Jiménez-Hernaiz  1   3 , Purificación Ros  2   4 , Alejandra Freire-Regatillo  1   2   3 , Vicente Barrios  1   3 , Jesús Argente  1   2   3   5 , Julie A Chowen  1   3   5
Affiliations

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice

Santiago Guerra-Cantera et al. Metabolites. .

Abstract

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.

Keywords: IGF1; IGF2; IGFBP2; high-fat diet; neuropeptides; obesity; sex differences.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Body weight progression (A) and accumulated weight gain in percentage (B) in male and female mice exposed to a high-fat diet (HFD), commercial control diet (CCD) or a chow diet for 8 weeks. *** p < 0.001; #: different from chow in the same sex, @: different between sexes on the same diet. n = 6.
Figure 2
Figure 2
Glucose tolerance test and insulin levels. Glucose levels over time (A), area under curve (B), plasma insulin levels (C) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR; D) in male and female mice on a high-fat diet (HFD), commercial control diet (CCD) or a chow diet for 8 weeks. a: overall effect of sex, b: overall effect of diet, #: different from chow on the same sex, @: differences between sexes on the same diet, n = 6.
Figure 3
Figure 3
Circulating levels of free IGF-1 (A), total IGF-1 (B), IGF2 (C), IGFBP2 (D) and IGFBP3 (E) in mice on a high-fat diet (HFD), commercial control diet (CCD) or chow diet for 8 weeks. *** p < 0.001, a: effect of sex, b: effect of diet, n = 6.
Figure 4
Figure 4
Relative gene expression of the insulin-like growth factor (IGF) system in visceral adipose tissue: IGF1 (A), IGF2 (B), IGF1R (C), IGF2R (D), IGFBP2 (E), PAPP-A (F), PAPP-A2 (G), stanniocalcin (STC)-1 (H) and STC-2 (I) in mice on a high-fat diet (HFD), commercial control diet (CCD) or a chow diet for 8 weeks. * p < 0.05, *** p < 0.001, a: effect of sex, b: effect of diet, ns = non-significant, n = 6.
Figure 5
Figure 5
Relative hypothalamic mRNA levels of the IGF system: IGF1 (A), IGF2 (B), IGF1R (C), IGF2R (D), IGFBP2 (E), IGFBP3 (G), IGFBP4 (H), IGFBP5 (I), PAPP-A (J), PAPP-A2 (K), STC-1 (L) and STC-2 (M). Correlation of relative hypothalamic mRNA levels of IGF2 and IGFBP2 (F). ** p < 0.01, b: effect of diet, ns = non-significant, HFD = high-fat diet, CCD = commercial control diet, n = 6.
Figure 5
Figure 5
Relative hypothalamic mRNA levels of the IGF system: IGF1 (A), IGF2 (B), IGF1R (C), IGF2R (D), IGFBP2 (E), IGFBP3 (G), IGFBP4 (H), IGFBP5 (I), PAPP-A (J), PAPP-A2 (K), STC-1 (L) and STC-2 (M). Correlation of relative hypothalamic mRNA levels of IGF2 and IGFBP2 (F). ** p < 0.01, b: effect of diet, ns = non-significant, HFD = high-fat diet, CCD = commercial control diet, n = 6.
Figure 6
Figure 6
Relative mRNA levels of orexigenic and anorexigenic neuropeptides in the hypothalamus: Neuropeptide Y (NPY; A), Agouti-related protein (AgRP; B), proopiomelanocortin (POMC; C) and cocaine and amphetamine regulated transcript (CART; D). b: effect of diet, ns = non-significant. HFD = high-fat diet; CCD = commercial control diet, n = 6.
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