Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jun 1;158(6):1766-1775.
doi: 10.1210/en.2016-1872.

Neural Programmatic Role of Leptin, TNFα, Melanocortin, and Glutamate in Blood Pressure Regulation vs Obesity-Related Hypertension in Male C57BL/6 Mice

Affiliations
Free PMC article

Neural Programmatic Role of Leptin, TNFα, Melanocortin, and Glutamate in Blood Pressure Regulation vs Obesity-Related Hypertension in Male C57BL/6 Mice

Bin Yu et al. Endocrinology. .
Free PMC article

Abstract

Continuous nutritional surplus sets the stage for hypertension development. Whereas moderate dietary obesity in mice is normotensive, the homeostatic balance is disrupted concurrent with an increased risk of hypertension. However, it remains unclear how the obesity-associated prehypertensive state is converted into overt hypertension. Here, using mice with high-fat-diet (HFD)-induced moderate obesity vs control diet (CD)-fed lean mice, we comparatively studied the effects of central leptin and tumor necrosis factor-α (TNFα) as well as the involvement of the neuropeptide melanocortin pathway vs the neurotransmitter glutamate pathway. Compared with CD-fed lean mice, the pressor effect of central excess leptin and TNFα, but not melanocortin, was sensitized in HFD-fed mice. The pressor effect of central leptin in HFD-fed mice was strongly suppressed by glutamatergic inhibition but not by melanocortinergic inhibition. The pressor effect of central TNFα was substantially reversed by melanocortinergic inhibition in HFD-fed mice but barely in CD-fed mice. Regardless of diet, the hypertensive effects of central TNFα and melanocortin were both partially reversed by glutamatergic suppression. Hence, neural control of blood pressure is mediated by a signaling network between leptin, TNFα, melanocortin, and glutamate and changes in dynamics due to central excess leptin and TNFα mediate the switch from normal physiology to obesity-related hypertension.

Figures

Figure 1.
Figure 1.
Effect of melanocortinergic inhibition on leptin-induced BP rise in obesity. Male C57BL/6 mice fed on a HFD for 3 months were implanted with a BP radio transmitter in the carotid artery and an injection cannula in the hypothalamic third ventricle. After 1 week of postsurgery recovery, mice received daily injection of leptin through the cannula for 2 consecutive days. On the second day of injection, HFD-fed mice received an intra–third-ventricle injection of SHU9119 vs vehicle 30 minutes prior to leptin administration. Curves on the left present the minute-by-minute average levels of (a) systolic, (b) diastolic, and (c) mean BP and (d) heart rate over a 4-hour postinjection period. Bar graphs on the right present average levels of (e) systolic, (f) diastolic, and (g) mean BP and (h) heart rate during two phases (35 to 65 minutes and 90 to 150 minutes after injection) of leptin-induced hypertension in HFD-fed mice. Phase 1 (35 to 65 minutes) is outlined by a gray dotted line (a–d), and phase 2 (90 to 150 minutes) is outlined by a red dotted line (a–d). Error bars reflect mean ± standard error of the mean. *P < 0.05, **P < 0.01; n = 5 mice per group. aCSF, artificial cerebrospinal fluid; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; Inj & Rec, injection and recovery; Lep, leptin; MBP, mean blood pressure; n.s., nonsignificant; SBP, systolic blood pressure; SHU, SHU9119.
Figure 2.
Figure 2.
Effect of glutamatergic inhibition on leptin-induced BP rise in obesity. Male C57BL/6 mice fed on a HFD for 3 months followed the same surgical procedure as described in Fig. 1. After 1-week postsurgery recovery, mice received daily intra–third-ventricle injection of leptin for 2 consecutive days. In the second day, mice received an intra–third-ventricle injection of KYN vs vehicle 30 minutes prior to leptin administration. Curves on the left present the minute-by-minute average levels of (a) systolic, (b) diastolic, and (c) mean BP and (d) heart rate over a 4-hour postinjection period. Bar graphs on the right present average levels of (e) systolic, (f) diastolic, and (g) mean BP and (h) heart rate during early and late phases (35 to 65 minutes and 105 to 165 minutes postinjection) of leptin-induced hypertension in HFD-fed mice. Phase 1 (35 to 65 minutes) is outlined by a gray dotted line (a–d), whereas phase 2 (105 to 165 minutes) is outlined by a red dotted line (a–d). Error bars reflect mean ± standard error of the mean. *P < 0.05, **P < 0.01; n = 5 mice per group. aCSF, artificial cerebrospinal fluid; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; Inj & Rec, injection and recovery; Lep, leptin; MBP, mean blood pressure; n.s., nonsignificant; SBP, systolic blood pressure.
Figure 3.
Figure 3.
Lack of hypertensive mechanism for central leptin in CD-fed lean mice. Male CD-fed C57BL/6 mice (with matched ages with HFD feeding) received the same surgical procedure as described in Figs. 1 and 2. After 1-week postsurgery recovery, mice received daily intra–third-ventricle injection of leptin for 2 days. On the second day of injection, mice were injected with SHU9119, KYN, or vehicle in the hypothalamic third ventricle 30 minutes prior to leptin injection. Curves on the left present the minute-by-minute average levels of (a) systolic, (b) diastolic, and (c) mean BP and (d) heart rate over a 4-hour postinjection period. Bar graphs on the right present average levels of (e) systolic, (f) diastolic, and (g) mean BP and (h) heart rate during early and late phases (35 to 65 minutes and 105 and 165 minutes postinjection) of leptin-induced hypertension in HFD-fed mice. Phase 1 (35 to 65 minutes) is outlined by a gray dotted line (a–d), and phase 2 (105 to 165 minutes) is outlined by a red dotted line (a–d). Error bars reflect mean ± standard error of the mean. n = 5 mice per group. aCSF, artificial cerebrospinal fluid; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; Inj & Rec, injection and recovery; Lep, leptin; MBP, mean blood pressure; SBP, systolic blood pressure; SHU, SHU9119.
Figure 4.
Figure 4.
Effect of melanocortinergic inhibition on TNFα-induced BP rise in obesity. Male C57BL/6 mice after 3-month HFD vs CD feeding received the same surgical procedure as described in Figs. 1–3. After surgery and recovery, mice received an intra–third-ventricle injection of SHU9119 vs vehicle 30 minutes prior to TNFα injection. Curves present the minute-by-minute average levels of (a, f) systolic, (b, g) diastolic, and (c, h) mean BP and (d, i) heart rate in (a–d) CD-fed vs (f–i) HFD-fed mice over a 4-hour postinjection period. Bars show the average levels of BP and heart rate in (e) CD-fed vs (j) HFD-fed mice during the 50 to 100 minutes postinjection outlined by a dotted line. Error bars reflect mean ± standard error of the mean. *P < 0.05, **P < 0.01; n = 5 mice per group. aCSF, artificial cerebrospinal fluid; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; Inj & Rec, injection and recovery; MBP, mean blood pressure; n.s., nonsignificant; SBP, systolic blood pressure; SHU, SHU9119; TNF, TNFα.
Figure 5.
Figure 5.
Effect of glutamatergic inhibition on TNFα-induced BP rise in obesity. Male C57BL/6 mice after 3-month HFD vs CD feeding received the same surgical procedure as described in Figs. 1–3. After surgery and recovery, mice received an intra–third-ventricle injection of KYN vs vehicle 30 minutes prior to TNFα injection. Curves present the minute-by-minute average levels of (a, f) systolic, (b, g) diastolic, and (c, h) mean BP and (d, i) heart rate in (a–d) CD-fed vs (f–i) HFD-fed mice over a 4-hour postinjection period. Bars show the average levels of BP and heart rate in (e) CD-fed (50 to 100 minutes postinjection) vs (j) HFD-fed (BP, 65 to 115 minutes postinjection; heart rate, 40 to 90 minutes postinjection) mice outlined by a dotted line (a–d, f–i). Error bars reflect mean ± standard error of the mean. *P < 0.05, **P < 0.01; n = 5 mice per group. aCSF, artificial cerebrospinal fluid; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; Inj & Rec, injection and recovery; MBP, mean blood pressure; n.s., nonsignificant; SBP, systolic blood pressure; TNF, TNFα.
Figure 6.
Figure 6.
Effect of glutamatergic inhibition on α-MSH-induced BP rise in obesity. Male C57BL/6 mice after 3-month HFD vs CD feeding received the same surgical procedure as described in Figs. 1–3. After surgery and recovery, mice received an intra–third-ventricle injection of KYN vs vehicle 30 minutes prior to α-MSH injection. Curves present the minute-by-minute average levels of (a, f) systolic, (b, g) diastolic, and (c, h) mean BP and (d, i) heart rate in (a–d) CD-fed vs (f–i) HFD-fed mice over a 4-hour postinjection period. Bars show the average levels of BP and heart rate in (e) CD-fed (85 to 155 minutes after injection) vs (j) HFD-fed (40 to 110 minutes after injection) mice outlined by a dotted line (a–d, f–i). Error bars reflect mean ± standard error of the mean. *P < 0.05, **P < 0.01; n = 5 mice per group. aCSF, artificial cerebrospinal fluid; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; Inj & Rec, injection and recovery; MBP, mean blood pressure; MSH, α-MSH; n.s., nonsignificant; SBP, systolic blood pressure.
Figure 7.
Figure 7.
Neural program in BP regulation vs obesity-related hypertension. Central control of BP in normal physiology involves neural actions of leptin and TNFα; whereas previous work revealed how the connection between leptin and TNFα affects BP, the current study further elucidates that leptin and TNFα also use the melanocortinergic pathway and glutamatergic pathway, respectively, to mediate the physiological control of BP. Crosstalk between these two processes at the level of the downstream neuronal circuitry was identified. In the obesity condition, increased leptin release activates glutamatergic neurons, which contributes to hypertension mainly independently of melanocortinergic neurons, whereas an obesity-associated increase in TNFα (partially due to high leptin level) activates melanocortinergic and glutamatergic neurons, both sequentially and in parallel, to mediate the induction of hypertension. Dotted lines indicate the weakened pathway in obesity compared with normal physiology. Bold lines indicate the pathways that become predominantly important steps in this complex mechanism in obesity. In general, glutamatergic activation is poised at the crossroad of translating obesity-related signals to hypertension and thus represents a critical target for combating obesity-related hypertension.

Similar articles

See all similar articles

Cited by 2 articles

Publication types

MeSH terms

Feedback