The cellular and molecular bases of leptin and ghrelin resistance in obesity

Abstract

Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.

Figure 1 |. Physiological functions of leptin and ghrelin.

Leptin and ghrelin are secreted from adipose tissue and from the stomach, respectively, enter the circulation and affect a wide range of physiological processes. In addition to direct peripheral targets, these hormones exert their actions in different regions of the brain, including several nuclei of the hypothalamus that are important for energy homeostasis, where both the ‘long’ form of the leptin receptor (LepRb) and the ghrelin receptor growth hormone secretagogue receptor (GHSR) are broadly expressed. The actions of the two hormones on their receptors regulate food intake and body weight, sympathetic nervous system tone and neuroendocrine responses, which in turn regulate physiological function of peripheral organs to coordinate homeostasis. 3v, third ventricle; ARC, arcuate nucleus of the hypothalamus; DMH, dorsomedial nucleus of the hypothalamus; LHA, lateral hypothalamic area; PVH, paraventricular nucleus of the hypothalamus; VMH, ventromedial nucleus of the hypothalamus.

Figure 2 |. LepRb signalling and the molecular mechanisms contributing to leptin resistance in obesity.

a | In individuals with normal body weight, circulating leptin crosses the blood–brain barrier (BBB) and binds to the ‘long’ form of the leptin receptor (LepRb), which induces phosphorylation of Janus kinase 2 (JAK2) and of multiple tyrosine residues in the LepRb intracellular domain. LepRb also receives inhibitory signals from multiple negative feedback loops (such as suppressor of cytokine signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B), PTP non-receptor type 2 (PTPN2), PTPe and exchange protein directly activated by cyclic AMP 1 (EPAC1)), ensuring that activation of LepRb does not go beyond a physiologically necessary point. b | In obesity, circulating levels of leptin increase, which is associated with diminished leptin transport across the BBB and activation of the inhibitory negative feedback systems that eventually lead to diminished LepRb signalling. Increased free fatty acids and chronic overnutrition cause lipotoxicity and endoplasmic reticulum (ER) stress, and trigger inflammatory responses that might contribute to a blunted physiological response to leptin in obesity. STAT3, signal transducer and activator of transcription 3.

Figure 3 |. Hypothalamic ghrelin signalling.

Ghrelin binds to growth hormone secretagogue receptor (GHSR) and stimulates hypothalamic sirtuin 1 (SIRT1)–p53 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)–AMP-activated protein kinase (AMPK) axes in the ventromedial nucleus of the hypothalamus (VMH). This action requires cannabinoid receptor 1 (CB1). Consequently, hypothalamic levels of malonyl-CoA, the physiological inhibitor of the enzyme carnitine palmitoyltransferase 1 (CPT1) isoforms A and C, are elevated. This effect promotes disinhibition of CPT1A, increases fatty acid oxidation, alters the levels of reactive oxygen species, increases expression of UCP2 and promotes the CPT1C-mediated increase in levels of ceramide. These metabolic changes activate the nuclear transcription machinery by increasing expression and/or activity of key transcription factors, such as cyclic AMP-responsive element-binding protein (CREB) and its phosphorylated isoform, pCREB, FOXO1, and brain-specific homeobox protein homologue (BSX) in the arcuate nucleus (ARC), increasing mRNA expression of AgRP and NPY, which induces feeding. Mechanistic target of rapamycin (mTOR) and k-opioid receptor (KOR) also mediate the effects of ghrelin in the ARC; however, the association between these two events is unclear. ACC, acetyl-CoA carboxylase; AgRP, agouti-related protein; ER, endoplasmic reticulum; NPY, neuropeptide Y; pAMPK, phosphorylated AMPK; pmTOR, phosphorylated mTOR.

Figure 4 |. Hypothalamic ghrelin resistance.

Obesity-associated ghrelin resistance might develop via different mechanisms, such as decreased circulating levels of ghrelin (1); impaired transport of ghrelin through the blood–brain barrier (BBB) (2); reduced expression of growth hormone secretagogue receptor (GHSR) (3); and reduced expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) (4), which reduces the orexigenic action of ghrelin. The molecular mechanisms leading to the reduction of neuropeptide expression are unclear, but possible candidates include hypothalamic inflammation, lipotoxicity, endoplasmic reticulum (ER) stress and impaired AMP-activated protein kinase (AMPK) or mechanistic target of rapamycin (mTOR) pathways. 3v, third ventricle; ARC, arcuate nucleus of the hypothalamus; DMH, dorsomedial nucleus of the hypothalamus; LHA, lateral hypothalamic area; PVH, paraventricular nucleus of the hypothalamus; VMH, ventromedial nucleus of the hypothalamus.