**4. Leptin release factors**

The immune system has a role in regulating energy expenditure and AT lipolysis [45]. White adipose tissue (WAT) is the primary energy store; brown adipose tissue (BAT) is associated with heat production. Sympathetic activity in WAT is increased in conditions associated with decreased leptin synthesis/secretion, such as cold exposure and starvation. By the way, catecholamine and β-adrenoceptor agonists inhibit leptin production; this suppressive effect is mediated by β3-adrenoceptor agonists, which actively reduce leptin levels [46]. Leptin also causes sympathetic nervous system activation, resulting in regulatory feedback inhibition [47]. Intracerebroventricular injections of leptin have been noted to increase metabolic rates through increased norepinephrine release from sympathetic nerve terminals innervating BAT [48].

After a meal, plasma insulin and amino acid levels initiate the mammalian target of rapamycin (mTOR) pathway, which stimulates leptin biosynthesis via mechanisms involving the 5′/3′ untranslated region (UTR) [49]. Cyclic AMP activates cyclic AMP-activated exchange proteins (EPACs). Deletion of *EPAC1* genes causes an increase in leptin sensitivity in the hypothalamus. *EPAC1* is also involved in leptin secretion and expression in WAT [50].

Leptin antagonizes orexigenic pathways and stimulates anorexigenic pathways. Leptin exerts its general effects on the nervous system through these pathways [7]. Orexigenic neuropeptides that are down-regulated by leptin are orexins, agouti-related peptides, neuropeptide Y, and melanin-concentrating hormone. By the way, the anorexigenic neuropeptides upregulated by leptin are alpha-melanocyte-stimulating hormone, which acts on corticotropin-releasing hormone, cocaine and amphetamine-regulated transcript, and melanocortin-4 receptor (**Figure 1**) [31].

Glucocorticoids are long-term regulators of leptin expression [52, 53]. They increase leptin mRNA levels by acting on adipocytes; *in vitro* incubation of a synthetic glucocorticoid in rats, adipocytes have been found to increase leptin secretion [54]. Oral glucocorticoids doubled serum leptin levels and leptin mRNA 24–48 hours after absorption. Furthermore, cell cultures incubated with a glucocorticoid and insulin combination synergistically increased leptin mRNA levels [55].

Lactates and hexoses also increase leptin secretion [56]. Because leptin secretion requires ATP, suppressing glucose uptake suppresses leptin secretion. When the energy supply is low, food is needed to increase it. Glucose, the cellular sensor of energy stock, stimulates leptin gene expression and secretion in both muscle and AT via hexosamine biosynthetic [57]. Insulin lowers blood sugar when glucose levels rise above normal and also increases leptin promoter activity [58]. No increase in leptin mRNA levels was observed after adipocytes were incubated with insulin for 1–2 hours, but an increase in leptin release was observed [54].

Regulation of tumor necrosis factor-alpha(TNFα) and leptin may be interdependent and similar as they have comparable functions such as suppressing

**Figure 1.**

*The leptin/Melanocortin pathway. ARC; the arcuate nucleus of the hypothalamus, POMC; proopiomelanocortin, Ob-R; leptin receptor, PVN; paraventricular nucleus, MSH; melanocyte-stimulating hormone (*α*-MSH,*β*-MSH,*γ*-MSH), MC4R; melanocortin-4 receptor, SIM1; single-minded 1 [51].*

lipid synthesis, reducing food intake, and stimulating lipolysis [59]. Leptin limits AT mass. TNFα has the role of stimulating leptin secretion from mature human adipocytes. TNFα therapy has been shown to cause increased leptin levels in humans [60].
