Hexarelin, a Growth Hormone Secretagogue, Improves Lipid Metabolic Aberrations in Nonobese Insulin-Resistant Male MKR Mice

Abstract

Despite the occurrence of dyslipidemia and its contribution to the development of insulin resistance in obese subjects, a growing number of studies have described abnormal lipid profiles among leaner persons. For example, individuals with an abnormal paucity or distribution of fat (lipodystrophy) develop severe insulin resistance, dyslipidemia, and hepatic steatosis. Deranged adipocyte metabolism and differentiation contribute to ectopic fat deposition and consequent development of insulin resistance. Growth hormone (GH) therapy has been shown to correct body composition abnormalities in some lipodystrophy patients. However, little is known about the effects of GH-releasing peptides in this regard. Hexarelin, a GH secretagogue, has recently been shown to have beneficial effects on fat metabolism via the CD36 receptor. In this study, the effects of twice daily intraperitoneal injections of hexarelin (200 μg/kg body weight) were examined in nonobese insulin-resistant MKR mice and corresponding wild-type FVB mice for 12 days. Hexarelin treatment significantly improved glucose and insulin intolerance and decreased plasma and liver triglycerides in MKR mice. These beneficial metabolic effects could be due to the improved lipid metabolism and enhanced adipocyte differentiation of white adipose tissue with hexarelin treatment. Interestingly, although food intake of hexarelin-treated MKR mice was significantly increased, this did not change total body weight. Moreover, hexarelin treatment corrected the abnormal body composition of MKR mice, as demonstrated by a decrease in fat mass and an increase in lean mass. Our results suggest a possible application of hexarelin in treatment of lipid disorders associated with the metabolic syndrome.

Figure 1.

Effects of twice daily IP injection of hexarelin (200 μg/kg BW) or saline for 12 days on (a) glucose tolerance test, (c) insulin tolerance test, and (e) pulsatile GH secretion in FVB saline (▪), FVB hex (□), MKR saline (●), and MKR hex (○). AUC of (b) GTT, (d) ITT, and (f) pulsatile GH secretion. Data are expressed as mean ± SEM (n = 5 to 6 per group). *P < 0.05, **P < 0.01, ****P < 0.0001 vs MKE saline group; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, ^####P < 0.0001 vs FVB saline group.

Figure 2.

Effects of hexarelin treatment on cumulative food intake of (a) FVB mice and (b) MKR mice measured from day −3 to day 12 of treatment in indirect calorimetric cages. Change in BW of (c) FVB mice and (d) MKR mice measured from day 0 (start of treatment) to day 12 of treatment. (e) Fat mass (% BW) and (f) lean mass (% BW) measured at day 12 of treatment. Data are expressed as mean ± SEM (n = 4 to 5 per group). *P < 0.05, **P < 0.01, ***P < 0.001 vs MKR saline group.

Figure 3.

Effects of hexarelin treatment on RER in (a) FVB mice, (d) RER in MKR mice, (g) total locomotor activity in FVB mice, and (j) total locomotor activity in MKR mice at days 0, 5, and 10 of treatment during dark phase (6:00 pm to 6:00 am) marked by shaded area in the graphs and light phase (6:00 am to 6:00 pm). AUC of RER during the (b) light and (c) dark phases of days 0, 5, and 10 of treatment in FVB mice. AUC of RER during the (e) light and (f) dark phases of days 0, 5, and 10 of treatment in MKR mice. AUC of locomotor activity during the (h) light and (i) dark phases of days 0, 5, and 10 of treatment in FVB mice. AUC of locomotor activity during the (k) light and (l) dark phases of days 0, 5, and 10 of treatment in MKR mice. Data are expressed as mean ± SEM (n = 4 per group). *P < 0.05 vs MKR saline group; ^##P < 0.01 vs FVB saline group at day 0.

Figure 4.

The effects of hexarelin treatment on (a) blood glucose, (b) plasma concentrations of insulin, (c) C-peptide, (d) ghrelin, (e) GLP-1, and (f) leptin at the end of treatment from terminal blood samples during fed conditions. Data are expressed as mean ± SEM (n = 4 to 6 per group). ^###P < 0.001, ^####P < 0.0001 vs FVB saline group.

Figure 5.

Effects of hexarelin treatment on (a) plasma FFAs, (b) plasma TGs, (c) plasma total cholesterol, and (d) plasma free cholesterol. Quantitative analyses of TGs in (e) liver and (f) muscles. Data are expressed as mean ± SEM (n = 4 to 7 per group). *P < 0.05 vs MKR saline group; ^#P < 0.05, ^##P < 0.01 vs FVB saline group.

Figure 6.

Fold changes in gene expression levels of PPAR-γ, PCG-1, FATP-4, CD36, LPL, HSL, and UCP-1 of WAT of (a) FVB and (b) MKR mice after treatment. The data were calculated using the 2^−ΔΔCT method. The results are presented as mean ± SEM (n = 5 to 6 per group). *P < 0.05, **P < 0.01 vs MKR saline group. (c) Hematoxylin and eosin staining of the gonadal fat pads from MKR and FVB mice treated with saline or hexarelin 12 days. Original magnification, ×10; scale bars, 100 μm. (d) Quantitative analysis of mean adipocytes area from 25 adipocytes per mouse. Data are expressed as mean ± SEM (n = 3 per group). **P < 0.01 vs MKR saline group. ^#P < 0.05 vs FVB saline group.