Leptin controls adipose tissue lipogenesis via central, STAT3–independent mechanisms

Buettner, Christoph; Muse, Evan D.; Cheng, Andrew; Gao, Xiang; Scherer, Thomas; Pocai, Alessandro; Su, Kai; Cheng, Bob; Li, Xiasong; Harvey−White, Judith; Schwartz, Gary J.; Kunos, George; Rossetti, Luciano

doi:10.1038/nm1775

Cited by 309 publications

(283 citation statements)

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“…The extent to which the adipocyte mTOR pathway also becomes resistant to insulin or nutrient signals may be a critical determinant of the ability of the adipocyte to upregulate leptin production and close the feedback loop. In addition, hypothalamic leptin signaling through PI 3-kinase can activate sympathetic nerves to regulate adipocyte lipogenesis and endocannabinoid production in adipose tissue (11). This mechanism may also regulate leptin transcription and translation, providing direct central control of leptin production and an additional feedback loop.…”

Section: Future Directionsmentioning

confidence: 99%

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Lee¹,

Fried²

2009

American Journal of Physiology-Endocrinology and Metabolism

113

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Lee M-J, Fried SK. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296: E1230 -E1238, 2009. First published March 24, 2009 doi:10.1152/ajpendo.90927.2008.-This review summarizes recent advances in our understanding of the pre-and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMPactivated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5Ј-and 3Ј-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production. adipose tissue; adrenergic; feeding; insulin; obesity LEPTIN IS A 16-KDA PROTEIN encoded by the obese (lep) gene that is expressed and secreted mainly by adipocytes. When energy stores are low, a fall in leptin decreases thermogenesis, promotes fatty acid (FA) over glucose oxidation, and decreases the activity of the hypothalamic pituitary adrenal and gonadal axes (1). Leptin also modulates the activities of the hematopoietic (5) and immune (52) systems, as well as angiogenesis (7).

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Section: Future Directionsmentioning

confidence: 99%

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Lee¹,

Fried²

2009

American Journal of Physiology-Endocrinology and Metabolism

113

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“…Many mechanisms have been proposed to explain the effect of leptin on peripheral glucose metabolism. Buettner et al proved that the cellular mechanisms underlying the hypothalamic regulation of hepatic glucose efflux depend on intact leptin STAT3 signaling [9]. A study by Morton et al indicates that hypothalamic leptin PI3K signaling is an important neuronal mechanism of glucose metabolism [10].…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that the sympathetic nervous system is involved in the transduction of leptin signals from the central nervous system to regulate peripheral glucose and lipid metabolism [9,48]. TH is a ratelimiting enzyme which synthesizes catecholamine.…”

Section: Discussionmentioning

confidence: 99%

“…High-fat diet (HFD)-induced leptin resistance and obesity may be mediated by defects in leptin in the Janus kinase 2 and signal transducer and activator of transcription (JAK2-STAT3) and the phosphatidylinositol 3-kinase (PI3K-Akt) signaling pathways in the hypothalamus [1, 6,7]. The JAK2-STAT3 pathway has been shown to mediate the effect of leptin on glucose metabolism [8], and the PI3K-Akt pathway is involved in both glucose [9] and lipid metabolism [10]. Recent studies have provided strong evidence for the contribution of hypothalamic inflammation to HFD-induced leptin resistance and/or type 2 diabetes mellitus [11,12].…”

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confidence: 99%

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Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice

Cheng

Zhang

et al. 2015

Molecular and Cellular Endocrinology

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X. (2015). Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice. Molecular and Cellular Endocrinology, Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice AbstractEpidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling. Disciplines Medicine and Health Sciences 2 AbstractEpidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids

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“…On the day of the clamp, conscious, unrestrained rats received the following MBH infusions at 0.33ul/h (CMA 400 syringe pump, CMA Microdialysis, Inc., North Chelmsford, MA): i) 0.9% Saline, ii) Glucose (Sigma-Aldrich, St. Louis, MO, 2mM for 6h; previously documented to lower glucose production (7)), iii) Glucose (2 mM) + leptin (R&D systems, Minneapolis, MN, 46 by guest on May 9, 2018 http://www.jbc.org/ Downloaded from ng/ul) (iv) lactate dehydrogenase blocker, oxamate (Millipore Sigma, Oakville, ON, Canada, 50 mM; first given as bolus (0.33ul)), (v) Glucose (2 mM) + oxamate (50 mM) or (vi) Glucose (2 mM) + leptin (46 ng/uL) + oxamate (50 mM). Leptin was infused at 33ng/h for 5h and this dose was chosen based on a previous study that reports leptin administered at 33 ng/h into the MBH for 6h exhibit metabolic control (31). In addition, we have chosen to infuse leptin 1h after glucose was started as we attempted to have the HFD rats first engage in glucose sensing mechanisms before examining whether leptin alters glucose sensing.…”

Section: Pancreatic (Basal Insulin)-euglycemic Clampsmentioning

confidence: 99%

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

Abraham

Rasti

Bauer

et al. 2018

Journal of Biological Chemistry

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Abstract:The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo. In both rodents and humans, glucose sensing is lost in diabetes and obesity but the site(s) of impairment remain elusive. We here first report that short-term high-fat feeding dirsupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased wholebody glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral-LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high-fat fed rats. In summary, our findings illustrate that leptin enhances LDH-A-dependent glucose sesning in the hypothalamus to lower glucose production in highfat fed rodents in vivo.The hallmark feature of Type 2 diabetes is traditionally viewed as insulin resistance resulting in elevated hepatic glucose production and impaired glucose uptake in peripheral tissues. However, a change in glucose responsiveness as defined as the ability of glucose sensing per se in regulating glucose production and uptake could also potentially contribute to glucose dysregulation in diabetes.For instance, studies conducted in both rodents and humans report that independent of changes in glucoregulatory hormones during the pancreatic clamps, a doubling of circulating glucose levels inhibits glucose production and stimulates peripheral glucose uptake in healthy conditions (1-3). However, the same increment in the plasma glucose levels fail to lower glucose production in diabetic rodents (1) and humans (2,3), thereby illustrating glucose unresponsiveness as a feature in diabetic conditions. Glucose unresponsiveness in obese individuals has been determined from a mathematical minimal model analysis following a frequently sampled intravenous (ivGTT) or oral glucose tolerance test. Indeed, a reduction in glucose responsiveness was associated with impaired glucose tolerance in obese individuals (4). As seen in humans, obese and diabetic rodents such as the leptin deficient ob/ob mice also display a loss of glucose sensing (5). Thus, the ability of glucose sensing per se to regulate its own metabolism is highly relevant in obesity and diabetes.To date, the site(s) of glucose sensing impairment that lead to glucose unresponsiveness in obesity and diabetes remain elusive. In this regard, a hypothalamic glucose sensing mechanism has been documented to maintain glucose homeostasis in the context of hypoglycemic-induced counter regulation (6) as well as short-t...

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Leptin controls adipose tissue lipogenesis via central, STAT3–independent mechanisms

Cited by 309 publications

References 48 publications

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

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