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

Abstract

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).

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

“…The cause of the leptin increase, however, is unknown. Leptin production is indirectly under insulin control via the PI3 K/AKT signalling pathway [8], and NRG1 stimulates this pathway in muscle cells [9]. ErbB2 activation upregulates leptin in human breast epithelial cells [4].…”

“…ErbB2 activation upregulates leptin in human breast epithelial cells [4]. However, it is not known whether NRG1 administration can affect white adipose tissue, the main leptin producer [8]. The fact that ErbB receptors are expressed in human preadipocytes [10] allows the assumption that adipose tissue may be involved in the NRG1-mediated increase in leptin.…”

Differential Signalling Through ALK-1 and ALK-5 Regulates Leptin Expression in Mesenchymal Stem Cells

“…Leptin was widely studied in 3T3-L1 mouse cell line described to have the potential to differentiate into adipocytes but with a low level of leptin mRNA expression [4]. Thus, recently, the need for a cell model that expresses leptin and robustly responds to hormonal signals for the study of leptin expression has emerged [3]. Our earlier study showed that SVF, belonging to mesenchymal lineages, expresses leptin, which is strongly enhanced by glucocorticoids [11].…”

“…In addition, it has been shown that leptin plays a role in regulating bone mass through osteogenic differentiation of mesenchymal progenitor cells [1,2]. Despite the fact that it was discovered in 1994, progress in understanding mechanisms of leptin expression has been slowed by the lack of cell lines that express leptin and respond robustly to hormonal signals [3]. Leptin was widely studied in 3T3-L1 mouse cell line described as having the potential to differentiate into adipocytes, but with a low level of leptin mRNA expression [4,5].…”

mTORC1 signaling in energy balance and metabolic disease

“…[88][89][90] Conversely, rapamycin impairs adipocyte differentiation by inhibiting PPARg transactivation activity. 88 Interestingly, leptin synthesis in the mature white adipocyte is also dependent on mTORC1 91 and, as suggested by Maya-Monteiro and Bozza, 92 mTORC1 could provide a positive feedback mechanism for the action of leptin on white adipocytes. On the other hand, full brown adipocyte differentiation requires AMPK activation associated with mTORC1 inhibition, although mTORC1 activation is essential during the first stages of differentiation.…”