Growth hormone secretagogue receptor deficiency in mice protects against obesity-induced hypertension

Abstract

Abstract Growth hormone secretagogue receptor (GHS-R) signaling has been associated with growth hormone release, increases in food intake and pleiotropic cardiovascular effects. Recent data demonstrated that acute GHS-R antagonism leads to increases in mean arterial pressure mediated by the sympathetic nervous system in rats; a highly undesirable effect if GHS-R antagonism was to be used as a therapeutic approach to reducing food intake in an already obese, hypertensive patient population. However, our data in conscious, freely moving GHS-R deficient mice demonstrate that chronic absence of GHS-R signaling is protective against obesity-induced hypertension. GHS-R deficiency leads to reduced systolic blood pressure variability (SBPV); in response to acute high-fat diet (HFD)-feeding, increases in the sympathetic control of SBPV are suppressed in GHS-R KO mice. Our data further suggest that GHS-R signaling dampens the immediate HFD-mediated increase in spontaneous baroreflex sensitivity. In diet-induced obesity, absence of GHS-R signaling leads to reductions in obesity-mediated hypertension and tachycardia. Collectively, our findings thus suggest that chronic blockade of GHS-R signaling may not result in adverse cardiovascular effects in obesity.

Keywords: Diet‐induced obesity; ghrelin; growth hormone secretagogue receptor; hypertension.

Figure 1

Growth hormone secretagogue receptor (GHS‐R) is critical for appropriate regulation of systolic blood pressure variability. Radio‐telemetry measurements in ad libitum chow fed, adult male wild‐type (WT, open bars) and GHS‐R KO (black bars) littermate mice. (A) Mean arterial pressure. (B) Heart rate. (C) Systolic blood pressure. (D) Spectral analysis of systolic blood pressure variability as LF/HF ratio. GHS‐R signaling is critical in the maintenance of appropriate autonomic control of blood pressure oscillations. (E) Spontaneous baroreflex sensitivity. Dark phase (9 pm–5 am)/light phase (9 am–5 pm) phase: two‐way repeated measures ANOVA for time and genotype, 24 h: t‐test; *P < 0.05 for genotype (WT n = 6; GHS‐R KO n = 8). (F) Diurnal corticosterone (CORT) profiles in WT (gray lines) and GHS‐R KO (black lines) mice (n = 8).

Figure 2

Growth hormone secretagogue receptor (GHS‐R) deficient mice are resistant to acute high‐fat diet (HFD)‐mediated increases in systolic blood pressure variability. Adult male WT (gray lines) and GHS‐R deficient mice (black lines) were fed a HFD for 12 days and dark‐phase cardiovascular parameters recorded every other day. (A) Body weight and food intake over 12‐day period. (B) Mean arterial pressure and heart rate. (C) Spectral analysis of systolic blood pressure variability (LF/HF ratio and HF and LF alone). While in WT mice SBPV increases over time of HFD‐feeding, this response is absent in GHS‐R KO, due, in most part, to a lack of increase in sympathetic control of blood pressure oscillations. (D) Spontaneous baroreflex sensitivity. sBRS is increased in both WT and GHS‐R KO mice in response to HFD‐feeding, however, this response appears increased in GHS‐R KO mice. Arrow indicates start of HFD‐feeding. (two‐way ANOVA repeated measures for time and genotype, *P < 0.05 for genotype, WT n = 6; GHS‐R KO n = 7).

Figure 3

Diet‐induced obese (DIO) Growth hormone secretagogue receptor (GHS‐R) deficient mice have lower MAP than their WT littermates despite similar body weights. Male adult WT and GHS‐R KO mice were fed a HFD for 12 weeks and cardiovascular parameters recorded every other day. (A) HFD‐fed WT and GHS‐R KO mice significantly increase in body weight and show fasting hyperglycemia (one‐way ANOVA, *P < 0.05, **P < 0.01, WT chow n = 9, WT HFD n = 10, GHS‐R KO n = 9). (B) Radio‐telemetry measurements in DIO WT and GHS‐R KO littermate mice after 12 weeks of HFD feeding. GHS‐R KO mice have lower MAP than WT littermates despite similar weight gain on HFD. (dark phase (9 pm–5 am)/light phase (9 am–5 pm) two‐way repeated measures ANOVA for time and genotype; 24 h t‐test; *P < 0.05 for genotype; WT n = 8; GHS‐R KO n = 6).

Figure 4

Growth hormone secretagogue receptor (GHS‐R) deficient mice are protected from HFD‐induced hypertension. Comparison of dark‐phase cardiovascular phenotypes in mice fed chow (white bars), HFD for 12 days (gray bars) or 12 weeks (black bars). (A) Mean arterial pressure and heart rate. GHS‐R deficient mice are protected against DIO‐mediated hypertension and increases in HR. (B) Power spectral analysis of SBPV. SBPV responses to diet are absent in GHS‐R KO mice. (C) Spontaneous baroreflex sensitivity. (two‐way ANOVA for diet and genotype; *P < 0.05, **P < 0.01, ***P < 0.001, WT n = 6–8, KO = 5–8).