Leptin receptor signaling: pathways to leptin resistance

Abstract

The identification of spontaneous mutations in the leptin- and leptin receptor (ObR)-encoding ob and db gene, respectively, opened up a new field in obesity research. Leptin, an adipocyte-derived hormone, mirrors the body's fat stores and thereby informs the brain about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations, like POMC and AgRP/NPY neurons, and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin is also involved in the regulation of other physiological processes including reproduction, bone homeostasis and immune function. Here, we review the pathways that are activated upon ObR activation, how ObR expression is controlled and the molecular mechanisms leading to leptin resistance, i.e. the inability to adequately respond to elevated leptin levels and therefore a primary risk factor for obesity.

Acute anorexigenic action of leptin in rainbow trout is mediated by the hypothalamic Pi3k pathway

“…Lep also stimulates Stat3 phosphorylation in the RTHy cells, as previously demonstrated in the rainbow trout hepatoma cell line RTH149 (Gong & Björnsson 2014). As Lep activates the Jak2-Stat3 and Pi3k-Akt pathways also in mammals (Wauman & Tavernier 2011), the current data show that these intracellular signaling mechanisms for Lep are evolutionarily conserved in vertebrates.…”

“…JAK2 activation allows LEPRb signaling via the signal transducers and activators of transcription (STAT), SHP2-mitogen-activated protein kinase, phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT), AMP-activated protein kinase, and the mammalian target of rapamycin (mTOR) pathways (Wauman & Tavernier 2011). Different LEP-responsive neurons activate and utilize differential signaling pathways, depending on physiological and nutritional states of the organism (Sahu 2011).…”

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

“…Alterations in the levels of adipokines including a decrease in adiponectin (Berg et al ., 2002) and increases in leptin (Wauman & Tavernier, 2011) and IL‐6 (Vozarova et al ., 2001) are primary links between obesity and systemic inflammation, as well as signs of progression of metabolic dysfunction. In contrast to the generally observed reciprocal relationship between obesity and adiponectin levels, Ames dwarf mice fed a HFD retained high levels of adiponectin when compared to control mice fed HFD ( P  < 0.0001) and did not differ from Ames dwarf mice fed STD ( P  = 0.15) (Fig.…”

Critically Discuss the Revival of Leptin for Obesity Therapy

“…However, none of these programmes has thus far proven to be effective in achieving the long-term weight loss (Kramer et al, 1989;Wooley & Garner, 1994;Curioni & Lourenco, 2005), implying that the exact causes of obesity are still unclear. A growing number of researchers have thus turned their attention to the study on the physiological mechanisms which normally regulate food intake and body weight, in the hope of identifying the real causes of obesity and discovering effective therapies Wauman & Tavernier, 2011;Myers, et al, 2012;Panariello et al, 2012;Wong et al, 2013; It is interesting that in most adults body weight is almost constant in spite of a large variation in daily food intake and energy expenditure (St-Pierre & Tremblay, 2012). Indeed, body weight is generally maintained within a narrow range by regulating a balance between energy intake, in the form of food and drinks, and energy expenditure, in the form of basal metabolism, physical activity and adaptive thermogenesis, via the adipose-tissue-brain crosstalk (Schwartz et al, 2000;Rosen & Spiegelman, 2006;Tao et al, 2011).…”