Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment

Choi, Sangdun; Yoon, Hana; Oh, Ki-Sook; Oh, Young Taek; Kim, Young I.; Kang, In‐Cheol; Youn, Jang H.

doi:10.1016/j.metabol.2010.02.013

Cited by 31 publications

(26 citation statements)

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“…1), suggesting that the NA-induced increase in corticosterone was mediated by ACTH. Plasma glucose was clamped at basal levels during NA infusion by glucose infusion (12); and therefore, the increases in plasma ACTH and corticosterone occurred without changes in plasma glucose.…”

Section: Resultsmentioning

confidence: 99%

“…Animals were housed under controlled temperature (22 Ϯ 2 C) and lighting [12-h light (0600 -1800 h), 12-h dark (1800 -0600 h) cycle] with free access to water and standard rat chow. At least 4 d before the experiment, the animals were placed in individual cages with tail restraints as previously described (11,12), which was required to protect tail blood-vessel catheters during the experiments. The animals were free to move about and were allowed unrestricted access to food and water.…”

Section: Animals and Catheterizationmentioning

confidence: 99%

“…In the experiments with NA or insulin infusion, plasma glucose was maintained at basal levels by exogenous glucose infusion (12). The plasma corticosterone and ACTH levels shown represent the averages of two samples taken during the final 30 min (45-and 60-min samples for corticosterone; 30-and 60-min samples for ACTH).…”

Section: Fig 1 Plasma Glucose (A) Glucose Infusion Rate (Ginf) (B)mentioning

confidence: 99%

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A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

Kang

et al. 2012

Endocrinology

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The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels. (Endocrinology 153: 3587-3592, 2012) T he brain plays a crucial role in energy homeostasis. When the blood glucose level falls, the brain senses it and activates various neuroendocrine mechanisms to restore blood glucose levels (1). These responses, known as glucose counterregulatory responses, are critical for the survival of the brain and have been extensively studied. According to the "selfish brain" theory (2), the brain places the highest priority on covering its own energy requirements when regulating energy homeostasis, activating stress responses upon a fall in cerebral energy (i.e. ATP) levels and suppressing insulin secretion to allocate glucose to the brain rather than the periphery. Free fatty acids (FFA) are another major fuel in mammals. It is established that FFA, like glucose, are sensed by the brain, and excess supply of FFA to the brain can suppress food intake and reduce hepatic glucose output (3). However, it is unclear whether the brain responds to a fall in plasma FFA, as it does with glucose, to activate mechanisms for its restoration. There is ample evidence that acute depression (or elevation) of plasma FFA stimulates (or inhibits) growth hormone secretion (4, 5). Because growth hormone is known to increase lipolysis in adipocytes, these effects of FFA on growth hormone secretion provide a negative feedback mechanism in the regulation of plasma FFA. The underlying mechanisms appear to be complex (4), but the brain (i.e. hypothalamus) may be responsible for at least some FFA effects (6). In addition, there are scattered data showing that nicotinic acid (NA) administration, which...

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Section: Resultsmentioning

confidence: 99%

Section: Animals and Catheterizationmentioning

confidence: 99%

Section: Fig 1 Plasma Glucose (A) Glucose Infusion Rate (Ginf) (B)mentioning

confidence: 99%

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A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

Kang

et al. 2012

Endocrinology

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“…In the current study, we set out to characterize changes in signaling regulation upon prolonged niacin treatment. We specifically investigated effects of niacin on adipose tissue as adipose tissue has been shown to be the most affected organ at the gene expression level after 7 h of niacin treatment ( 18 ).…”

Section: Quantitative Pcrmentioning

confidence: 99%

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Heemskerk

Dharuri

Berg

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words drug therapy/hypolipidemic drugs • adipocytes • fatty acid/biosynthesis • omega-3 fatty acids • cytochrome P450 • polyunsaturated fatty acid Niacin (vitamin B3) treatment reduces CVD and atherosclerosis development ( 1 ). These benefi cial effects are mediated, in part, by lowering circulating levels of LDLcholesterol, VLDL-TG, and lipoprotein(a) ( 2 ), as well as by increasing HDL-cholesterol ( 3 ). In addition, prolonged niacin treatment also decreases plasma, adipose tissue, and vascular infl ammation ( 4, 5 ), which might contribute to reducing CVD. The induction of these benefi cial effects after prolonged niacin treatment is in striking contrast to the unwanted acute niacin effects.Acutely, niacin binds to the inhibitory hydroxycarboxylic acid receptor 2 (HCA 2 ) (previously known as GPR109A). In adipocytes, this leads to an inhibition of adipocyte lipolysis followed by an acute reduction of plasma nonesterifi ed fatty acid (NEFA) levels. Lowering NEFA levels causes metabolic stress ( 6, 7 ), which increases stress hormone levels ( 8-12 ) after niacin treatment. In the skin Langerhans cells and keratinocytes, acute niacin binding to the

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“…One goal of the present study was to develop an animal model of FFA rebound during continuous NA administration. Our recent study (12) showed that the ability of NA to lower plasma FFA was maintained for up to 7 h when NA was constantly infused in rats. In the present study, we extended this infusion to 24 h and tested whether this prolonged exposure to NA would cause an FFA rebound.…”

mentioning

confidence: 98%

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Choi

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue. Am J Physiol Endocrinol Metab 300: E1012-E1021, 2011. First published March 8, 2011; doi:10.1152/ajpendo.00650.2010.-Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipidlowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (Ͼ60%, P Ͻ 0.01), and this effect was maintained for Ն5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P Ͻ 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment. hypolipidemic drug; free fatty acids; perilipin; phosphodiesterase; triglyceride synthesis; insulin resistance; nicotinic acid receptor; microarray analysis NICOTINIC ACID (NA; or niacin) is a B-group vitamin. In addition to its function as a vitamin, NA, in high doses, has been used as a lipid drug for five decades (6, 21); it produces very desirable effects such as decreasing plasma triglycerides (TG), VLDL, and LDL-cholesterol levels and increasing HDL-cholesterol levels (14,38). Major clinical trials have demonstrated that NA treatment reduces the progression of atherosclerotic cardiovascular disease (9, 18). The lipid-lowering effects of NA have traditionally been attributed to its antilipolytic effect in adipocytes (10). NA binds to and stimulates a G proteincoupled receptor [i.e., GPR109A or HM74A (37, 41)] in the plasma membrane of adipo...

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Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment

Cited by 31 publications

References 51 publications

A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

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