Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet-Induced Obesity

Zhao, Dan; McCully, Belinda H.; Brooks, Virginia L.

doi:10.1124/jpet.112.194738

Cited by 24 publications

(32 citation statements)

References 55 publications

(77 reference statements)

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“…Our present and previous findings show that OP rats fed a short-term HFD do not develop arterial hypertension, but exhibited severely impaired cardiac baroreflex function and autonomic imbalance (25,41), similar to human obesity (1,15,36). This suggests that changes in autonomic tone may precede, and perhaps be causal, in the development of hypertension in obesity (14,20,21).…”

Section: Discussionmentioning

confidence: 47%

“…Excessive weight gain in OP rats is attributed to a high food intake and a dysregulation of energy balance, most likely due to central overexpression of neuropeptide Y (23). Furthermore, OP rats have insulin resistance (6,9,22,41) and lower rates of fat oxidation (6), modeling the characteristics of human obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Rats (57-59 days, 250 -275 g) were placed on a HFD (33% kcal fat, Purina 571R, Richmond, IN) for 4 -6 wk, as previously described (25,41). After 2 wk, the bottom tertile of weight gain was classified as the OR group, while the top tertile was classified as the OP group.…”

Section: Dio Modelmentioning

confidence: 99%

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Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias

McCully

Hasan

Streiff

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Obesity increases the risk of arrhythmias and sudden cardiac death, but the mechanisms are unknown. This study tested the hypothesis that obesity-induced cardiac sympathetic outgrowth and hyperinnervation promotes the development of arrhythmic events. Male Sprague-Dawley rats (250-275 g), fed a high-fat diet (33% kcal/fat), diverged into obesity-resistant (OR) and obesity-prone (OP) groups and were compared with rats fed normal chow (13% kcal/fat; CON). In vitro experiments showed that both OR and OP rats exhibited hyperinnervation of the heart and high sympathetic outgrowth compared with CON rats, even though OR rats are not obese. Despite the hyperinnervation and outgrowth, we showed that, in vivo, OR rats were less susceptible to arrhythmic events after an intravenous epinephrine challenge compared with OP rats. On examining total and stimulus-evoked neurotransmitter levels in an ex vivo system, we demonstrate that atrial acetylcholine content and release were attenuated in OP compared with OR and CON groups. OP rats also expressed elevated atrial norepinephrine content, while norepinephrine release was suppressed. These findings suggest that the consumption of a high-fat diet, even in the absence of overt obesity, stimulates sympathetic outgrowth and hyperinnervation of the heart. However, normalized cardiac parasympathetic nervous system control may protect the heart from arrhythmic events.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 99%

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Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias

McCully

Hasan

Streiff

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…In the present chronic study, significant reductions in cardiac baroreflex sensitivity occurred only after several days of highfat intake and presumably sustained hyperlipidemia, suggesting that increased circulating lipids from dietary sources may not have immediate direct actions to depress baroreflex function. Given the increased plasma levels of insulin and plasma renin activity measured after 7 days of fat feeding when postabsorptive blood samples were first taken in the present study (33), the early impairment of cardiac baroreflex function during the high-fat diet may be a secondary response to central insulin resistance (12,62) and/or the central actions of angiotensin II (48). Furthermore, with progressive weight gain, impairment of the cardiac baroreceptor reflex may be attributed to adipose tissue-derived inflammatory cytokines/hormones such as leptin and interleukin-6, which act in the nucleus tractus solitarii to inhibit the baroreflex (2,53).…”

Section: Discussionmentioning

confidence: 99%

Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension

Iliescu

Tudorancea

Irwin

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Iliescu R, Tudorancea I, Irwin ED, Lohmeier TE. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am J Physiol Heart Circ Physiol 305: H1080 -H1088, 2013. First published August 2, 2013; doi:10.1152/ajpheart.00464.2013.-The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation-current therapies in patients with resistant hypertension, who are commonly obese-restore cardiovascular dynamic control. Increases in body weight to ϳ150% of control led to a gradual increase in mean arterial pressure to 17 Ϯ 3 mmHg above control (100 Ϯ 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1-4 days on high-fat intake, reaching 130 Ϯ 4 beats per minute (bpm) (control ϭ 86 Ϯ 3 bpm) and ϳ45% and Ͻ20%, respectively, of control levels. Subsequently, both baroreflex activation and renal denervation abolished the hypertension. However, only baroreflex activation effectively attenuated the tachycardia and restored cardiac baroreflex sensitivity and heart rate variability. These findings suggest that baroreflex activation therapy may reduce the risk factors for cardiac arrhythmias as well as lower arterial pressure. obesity; hypertension; heart rate variability; baroreflex; sympathetic nervous system THE CAUSAL LINK between obesity and hypertension is well recognized. Clinical and experimental evidence also indicate that obesity has a profound impact on cardiac automaticity (44), which may increase the risk for atrial and ventricular arrhythmias, leading causes of morbidity and mortality in the industrialized world (4,7,17,42,59,60). The mechanisms that mediate the proarrhythmogenic effects of obesity have received little attention. Low heart rate variability has been identified not only as a predictor of but also as a risk factor for developing life-threatening cardiac arrhythmias (7,8,26,46,50,56,57) and, together with impaired baroreflex control of heart rate, is a common finding in obese individuals (6,18,20,51,58). Alterations in cardiac autonomic neural regulation are the substrate for reductions in both heart rate variability and baroreflex sensitivity and, consequently, may increase risk for cardiac arrhythmias (7,8). While sustained activation of the sympathetic nervous system has been shown t...

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“…This is reminiscent of rosiglitazone-treated WT-DIO mice, which are insulin sensitive but obese (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Pancreastatin-Dependent Inflammatory Signaling Mediates Obesity-Induced Insulin Resistance

Bandyopadhyay

Avolio

et al. 2014

Diabetes

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Chromogranin A knockout (Chga-KO) mice exhibit enhanced insulin sensitivity despite obesity. Here, we probed the role of the chromogranin A-derived peptide pancreastatin (PST: CHGA ) by investigating the effect of diet-induced obesity (DIO) on insulin sensitivity of these mice. We found that on a high-fat diet (HFD), Chga-KO mice (KO-DIO) remain more insulin sensitive than wild-type DIO (WT-DIO) mice. Concomitant with this phenotype is enhanced Akt and AMPK signaling in muscle and white adipose tissue (WAT) as well as increased FoxO1 phosphorylation and expression of mature Srebp-1c in liver and downregulation of the hepatic gluconeogenic genes, Pepck and G6pase. KO-DIO mice also exhibited downregulation of cytokines and proinflammatory genes and upregulation of anti-inflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced proinflammatory gene expression. The insulin-sensitive, anti-inflammatory phenotype of KO-DIO mice is masked by supplementing PST. Conversely, a PST variant peptide PSTv1 (PST-ND3: CHGA 276-301 ), lacking PST activity, simulated the KO phenotype by sensitizing WT-DIO mice to insulin. In summary, the reduced inflammation due to PST deficiency prevented the development of insulin resistance in KO-DIO mice. Thus, obesity manifests insulin resistance only in the presence of PST, and in its absence obesity is dissociated from insulin resistance.The chromogranin A (human CHGA/mouse Chga) proprotein (1-4) undergoes proteolysis and gives rise to bioactive peptides including the antihypertensive catestatin (CHGA 352-372 ) (5-8) and the diabetogenic pancreastatin (PST: CHGA 250-301 ) (9-12). We have shown that Chgadeficient mice (Chga-KO) are obese, hyperadrenergic, and hypertensive. They display elevated levels of circulating leptin and catecholamines but lower levels of interleukin (IL)-6 and Mcp-1 (11,13-16). Despite these abnormalities, Chga-KO mice exhibit enhanced insulin sensitivity (11), a phenotype masked by supplementing PST. PST regulates hepatic insulin signaling through conventional (c) PKC and Srebp-1c (11). Increased plasma PST levels in diabetic populations correlate with insulin resistance (10). Similarly, increased circulating levels of PST in diet-induced obesity (DIO) and db/ db mice are associated with insulin resistance. Despite high levels of plasma leptin and catecholamines, Chga-KO mice are obese owing to peripheral leptin and catecholamine resistance (17).Since normal chow diet (NCD)-fed Chga-KO mice displayed increased insulin sensitivity (11), we hypothesized that Chga-KO mice may be able to maintain insulin sensitivity when exposed to the dysglycemic stress of a highfat diet (HFD). The hallmarks of insulin resistance in DIO mice are obesity, hyperinsulinemia, and increased inflammation (18)(19)(20)(21)(22). Suppression of inflammation in DIO mice can improve insulin sensitivity (23-25). For example, rosiglitazone can improve inflammation and insulin sensitivity in DIO mice without reducing obesity significantly (23-25). Chga-KO mice are...

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Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet-Induced Obesity

Cited by 24 publications

References 55 publications

Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias

Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias

Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension

Pancreastatin-Dependent Inflammatory Signaling Mediates Obesity-Induced Insulin Resistance

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