Somatotropic Axis Dysfunction in Non-Alcoholic Fatty Liver Disease: Beneficial Hepatic and Systemic Effects of Hormone Supplementation

Daniel Cabrera, Claudio Cabello-Verrugio, Nancy Solís, Diego San Martín, Catalina Cofré, Margarita Pizarro, Juan Pablo Arab, Johanna Abrigo, Fabián Campos, Betzabé Irigoyen, Gonzalo Carrasco-Avino, Katiuska Bezares, Valentina Riquelme, Arnoldo Riquelme, Marco Arrese, Francisco Barrera, Daniel Cabrera, Claudio Cabello-Verrugio, Nancy Solís, Diego San Martín, Catalina Cofré, Margarita Pizarro, Juan Pablo Arab, Johanna Abrigo, Fabián Campos, Betzabé Irigoyen, Gonzalo Carrasco-Avino, Katiuska Bezares, Valentina Riquelme, Arnoldo Riquelme, Marco Arrese, Francisco Barrera

Abstract

Background: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model.

Methods: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 µg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured.

Results: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia).

Conclusions: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model.

Keywords: IGF-1; fatty liver; growth hormone; insulin growth factor 1; somatotropic axis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Metabolic effects of intervention according to study groups: (A) Body weight; (B) Liver weight; (C) Serum Glucose; (D) Serum Insulin and (E) Homeostasis Model Assessment of Insulin resistance (HOMA-IR). High fat diet (HFD) induced a significant increase in body weight and HOMA-IR. HFD induced hepatomegaly and a significant increase in serum insulin. * p < 0.05; ** p < 0.01.
Figure 2
Figure 2
Effects of somatotropic hormone supplementation in liver. (A) Representative histological images of livers from experimental groups after 22 weeks of feeding with either chow, high fat diet (HFD) and HFD supplemented with growth hormone GH or insulin-like growth factor-1 (IGF-1). (B) Quantification of liver steatosis by histology in percentage of steatotic hepatocytes in experimental groups. No significant increase in steatosis can be observed in HFD + IGF-1 group compared to Chow. (C) Histology Score. No significant changes were observed in liver inflammation, ballooning and fibrosis in histology. (D) Hepatic triglycerides content according to experimental groups. A significant reduction of triglycerides content was observed in HFD + GH group. (E) Effects of hormone supplementation in lipogenic gene expression. A significant reduction was observed in HFD + GH group compared to HFD. (F) Serum ALT levels according to experimental groups. A significant reduction was observed in HFD + GH and HFD + IGF-1 groups compared to HFD. * p < 0.05; ** p < 0.01.
Figure 3
Figure 3
High fat diet induced sarcopenia that was fully reverted by somatotropic hormone supplementation. (A) Muscle histological sections with wheat germ agglutinin (WGA) fluorescence staining, (B) muscle fibre diameter distribution as determined by measure of the minimal feret’s diameter, (C) analysis of three muscle fibre size ranges. Thick (>56 Lm), medium size (30–55 Lm), and thin (<30 Lm) muscle fibres are shown. (D,E) electrophysiological analysis of TA muscle strength from both groups including twitch and tetanus contractions. (F) Body strength in vivo. * p < 0.05; ** p < 0.01; N.D., not detectable.
Figure 4
Figure 4
Serum adipokines levels: (A) Leptin and (B) adiponectin. Growth hormone supplementation attenuated high fat diet (HFD) associated increase of leptin serum levels, and reduced serum adiponectin levels compared to HFD and HFD + IGF-1. * p < 0.05; ** p < 0.01.
Figure 5
Figure 5
(A) Schematic representation of experimental approach on each of the study groups. (B) Implantation of osmotic pumps. Osmotic pumps were implanted subcutaneously in C56BL6 mice after 12 weeks of high fat diet for continuous subcutaneous infusion of placebo, growth hormone (GH) or insulin growth factor type 1 (IGF-1) respectively. HFD: High fat diet.

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