Leptin

Leptin (LEP, LEPD, OBS) is a 167-amino-acid peptide (16 kDa) that is mainly produced in white adipose tissue (thus one of “adipokines”), but also in other tissues, including placenta, mammary gland, brown adipose tissue, ovary, skeletal muscle, stomach, pituitary gland, bone marrow, and lymphoid tissue. Subcutaneous adipose tissue produces more leptin than visceral adipose tissue. Leptin plays an important role in regulating energy homeostasis, neuroendocrine, and immune functions, and glucose, lipid, and bone metabolism.

Leptin concentration in the blood is proportional to the amount of body fat, but fluctuate according to changes in calorie intake (decreased rapidly during fasting) and circadian rhythm with the lowest concentration at mid-afternoon and highest concentration after midnight (Park & Ahima, 2015). In obesity, circulating leptin levels are high, but fail to reduce weight gain (“leptin resistance”); also exogenous leptin administration does not reduce body fat content in obese individuals. High leptin levels predict worsening of metabolic syndrome independently of obesity. The cerebrospinal fluid-to-plasma ratio of leptin is decreased, suggesting reduced leptin transport across the blood-brain barrier. In preclinical models of obesity, intrathecal leptin administration directly to the cerebrospinal fluid reduces food intake. Injection of [68Ga]leptin into the lumbar space of baboons proved that intrathecal administration of leptin can reach the hypothalamus in therapeutic concentrations (McCarthy et al., 2002).

Leptin modulates innate and adaptive immune functions by stimulating neutrophil chemotaxis, promoting macrophage phagocytosis, and stimulating production of pro-inflammatory cytokines, such as IL-6, IL-12, and TNF-α. Leptin may contribute to the development of autoimmune diseases: for example, leptin treatment potentiates the EAE animal model of multiple sclerosis. Low levels of leptin in malnourished individuals may contribute to increased risk of infections and insufficient cell-mediated immune functions.

Leptin is cleared from circulation by the kidneys. Blood concentration is elevated in renal failure patients. In renal glomeruli, leptin passes through the filter, and is taken up by proximal convoluted tubules in megalin- and clathrin-mediated saturable endocytosis (Ceccarini et al., 2009). LepRs are found in later parts of renal tubular system and collecting ducts, where leptin may increase diuresis and natriuresis. After reuptake, leptin is degraded in a saturable process (Hama et al., 2004).

Metreleptin is an analogue of human leptin, which can be used for treatment of leptin deficiency.

Leptin receptors

Six alternatively spliced isoforms of leptin receptor (LepR, ObR) have been identified, LepRa-LepRf. LepRs are heavily glycosylated, while leptin is not. The long isoform (LepRb) is highly expressed in the brain, especially in the hypothalamus, where leptin suppresses food intake and stimulates energy expenditure. LepRb expression is high also on hematopoietic cells and immune cells. LepRe (ObRe) is a soluble form, which in humans is generated by ectodomain shedding. The short isoforms of leptin receptor (LepRa, LepRc, LepRd, LepRf), have shorter intracellular domain, and lack the intracellular signalling domain. These slice variants have broader tissue distribution, including the kidneys, liver, lungs, and spleen. LepRa is expressed on cerebral microvessels and choroid plexus, and has been thought to mediate transport of leptin across the BBB, but other mechanism for the brain access of leptin can be present as well, including megalin (LRP2) (Flavell, 2009; Wauman et al., 2017). Mutations that cause the loss of function of leptin or leptin receptors result in severe early-onset obesity, but also abnormalities in immune functions, reproduction, angiogenesis, and bone formation (Wauman et al., 2017).

Only 10-20% of leptin receptors are located at the cell membrane, because of partial retention of the protein in the synthesis pathway, and because of constitutive endocytosis of the receptor, independent on the ligand. Like many other cytokine receptors, LepRs can form inactive dimers or oligomers (Wauman et al., 2017).

Leptin, GLP-1, and cholecystokinin (CCK) act synergistically to promote satiety. Leptin affects the mesolimbic dopamine system both directly and indirectly, reducing the hedonic drive to eating. Low leptin level during fasting suppresses thyroid and growth hormone levels. Energy expenditure is increased through leptin action on sympathetic nervous system. In rodents, leptin stimulates brown adipose tissue. Via sympathetic nervous system, leptin also stimulates lipolysis in white adipose tissue and liver. Leptin receptors are expressed in brown and white adipose tissue (at least in mice), and leptin inhibits the actions of insulin in these tissues, resulting in reduced glucose uptake. Leptin reduces glucagon secretion from pancreatic α-cells (possibly through indirect mechanisms) and inhibits insulin synthesis and secretion from β-cells. LepR expression is higher in somatostatin releasing pancreatic δ-cells than in α- and β-cells (D’souza et al., 2017). Insulin stimulates leptin synthesis and secretion in adipose tissue. In skeletal muscle, leptin increases glucose uptake and fatty acid oxidation. In the liver, leptin suppresses glucose production. In the bone, leptin acts both centrally and peripherally; osteoblast proliferation, differentiation, and mineralization is stimulated, and bone marrow adipocyte differentiation is inhibited.

Leptin receptors are present in atherosclerotic lesions. Leptin promotes the recruitment of monocytes and formation of foam cells.

PET imaging

Leptin has been labelled with 68Ga (McCarthy et al., 2002) and 18F (Flavell et al., 2008; Ceccarini et al., 2009). After intravenous administration, no brain uptake was seen in mice, and the uptake of both tracers was highest in the renal cortex, and moderate in the liver and spleen. No uptake was seen in the adipose tissue. The metabolites of [68Ga]DOTA-leptin remained in the kidneys for an extended period, while [18F]FBA-leptin was not trapped. Metabolites of [18F]FBA-leptin are excreted in urine. Co-injection of cold ligand reduced the renal retention of 68Ga, and led to increased concentration of intact [68Ga]DOTA-leptin in the urine (Ceccarini et al., 2009). Biodistribution study in mice using [125I]leptin confirmed saturable uptake in the spleen, lungs, liver, femur (thigh bone), and low levels in the brain and adipose tissue (Ceccarini et al., 2009). In rhesus macaques, [68Ga]DOTA-leptin and [18F]FBA-leptin uptake was again highest in the renal cortex, and high uptake was also detected in the red bone marrow. Bone marrow uptake is saturable, but there is no saturable uptake in the heart (Ceccarini et al., 2009).

The effects of leptin on metabolism can be studied with specific PET tracers. For instance, an association between blood leptin levels and coronary vasoreactivity have been observed with myocardial perfusion measurement using [15O]H2O PET (Sundell et al., 2003).


See also:



References:

Ceccarini G, Flavell RR, Butelman ER, Synan M, Willnow TE, Bar-Dagan M, Goldsmith SJ, Kreek MJ, Kothari P, Vallabhajosula S, Muir TW, Friedman JM. PET imaging of leptin biodistribution and metabolism in rodents and primates. Cell Metab. 2009; 10: 148-159. doi: .

D’souza AM, Neumann UH, Glavas MM, Kieffer TJ. The glucoregulatory actions of leptin. Mol Metab. 2017; 6: 1052-2065. doi: 10.1016/j.molmet.2017.04.011.

Flavell RR. Novel Interactions of the Hormone Leptin Revealed by PET Imaging in Rodents and Rhesus Macaques. Student Theses and Dissertations, 2009, Paper 112.

La Cava A. Leptin in inflammation and autoimmunity. Cytokine 2017; 98: 51-58. doi: 10.1016/j.cyto.2016.10.011.

Nicholson T, Church C, Baker DJ, Jones SW. The role of adipokines in skeletal muscle inflammation and insulin sensitivity. J Inflamm. 2018; 15:9. doi: 10.1186/s12950-018-0185-8.

Pandit R, Beerens S, Adan RA. Role of leptin in energy expenditure: the hypothalamic perspective. Am J Physiol Regul Integr Comp Physiol. 2017; 312: R938-R947. doi: 10.1152/ajpregu.00045.2016.

Park H-K, Ahima RS. Physiology of leptin: energy homeostasis. neuroendocrine function and metabolism. Metabolism 2015; 64: 24-34. doi: 10.1016/j.metabol.2014.08.004.

Wauman J, Zabeau L, Tavernier J. The leptin receptor complex: heavier than expected? Front Endocrinol. 2017; 8:30. doi: 10.3389/fendo.2017.00030.



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Created at: 2018-08-05
Updated at: 2018-10-26
Written by: Vesa Oikonen