Whereas leptin has been successfully used in the treatment of leptin-deficient obese patients, trials in hyperleptinemic obese patients have yielded variable results. Long-acting leptins have been tried but with no greater success.
Full Answer
Is there a clinical utility of leptin in obesity?
The inability of this circulating leptin to exert its anorexigenic effects in obese individuals shows that there is a lack of clinical utility of leptin in obesity. This is defined as leptin resistance.
Does obesity affect leptin transport across the blood-brain barrier?
Obesity is Associated With a Decreased Leptin Transport Across the Blood-Brain Barrier in Rats. Diabetes (2000) 49:1219–23. 10.2337/diabetes.49.7.1219 [ PubMed] [ CrossRef] [ Google Scholar]
Why can’t leptin be taken as a supplement?
Because leptin is a digestible protein that doesn’t enter the bloodstream, it can’t be taken in supplement form, Atkinson says. “If you were to take it as a pill, it’s just like eating chicken or beef. It’s a protein and your body would just break it up, so you wouldn’t absorb it from a pill.”
Is leptin overexpressed in adipose tissue?
Leptin is overexpressed at the gene level in the adipose tissue of individuals with obesity ( 86 ). Furthermore, strong positive associations exist between plasma leptin levels and body fat percentage ( 87, 88 ).
How can leptin be used to treat obesity?
Synergistic effects of leptin and amylin promote weight loss while preventing the compensatory reduction in energy expenditure associated with weight loss (138, 148). The combined therapy of leptin and pramlintide (an amylin analog) results in more weight loss in subjects with obesity than either treatment alone.
What role does leptin play in weight management quizlet?
Leptin is a hormone that acts to reduce food intake and to decrease body weight and body fat.
What is the relationship between leptin and obesity?
The levels of leptin, a major regulator of lipid metabolism, may increase in obesity, and contribute to the development of metabolic syndrome. Leptin is produced by adipose tissue and is a peptide hormone, which has strong association with obesity, elevated cardiovascular risk, and morbidity.
Do obese people have leptin resistance?
Yet, people who are obese often develop leptin resistance. Their leptin levels are elevated, but their brain cannot recognize the hormone's signal to stop eating. Most leptin supplements don't contain the hormone but rather a mix of nutrients that may improve leptin sensitivity.
What leptin is used for quizlet?
Leptin is a hormone produced by adipose cells. What does leptin do? It regulates fat stores within the body by suppressing appetitite.
What is the major role of leptin in the body?
The circulating leptin level serves as a gauge for energy reserves and directs the central nervous system to adjust food intake and energy expenditure accordingly. Leptin exerts immediate effects by acting on the brain to regulate appetite (Figure 1).
Is leptin treatment an option in treating obesity due to genetic causes?
Leptin therapy is useful in treating obesity related to congenital leptin deficiency. Leptin has been recently approved for lipodystrophy, which is a model for typical obesity. Typical obesity presents with leptin resistance but leptin may still be valuable after weight loss or in conjunction with other therapies.
What stimulates leptin production?
Leptin secretion Insulin stimulates leptin secretion through a posttranscriptional mechanism that is mainly mediated by the PI3K-PKBmTOR pathway, or other unknown pathways. It has been suggested that the chronic effect of insulin is mediated by glucose metabolism.
How does leptin resistance develop?
Mechanisms underlying the development of leptin resistance include mutations in the genes encoding leptin and its receptors, as well as proteins involved in self-regulation of leptin synthesis and blood–brain barrier permeability.
Abstract
The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis.
Introduction
Obesity-associated co-morbidities such as hypertension, dyslipidemia, type 2 diabetes mellitus, fatty liver disease, heart disease, and some types of cancer cause about 3.4 million adults (over age 18) deaths in 2016, according to the World Health Organization ( 1 ).
Leptin and Its Cognate Receptor
The leptin molecule is 16 kDa in size and comprises 167 amino acids (including a 21 amino acid secretory signal sequence), and it exhibits the tertiary structure of a globular protein ( 18, 19 ).
Leptin and Obesity
Severe early obesity develops from rare genetic mutations that affect leptin signaling ( 2, 83 ). Such mutations often lead to congenital leptin deficiency or high but ineffective leptin and leptin resistance ( 84 ). Hyperleptinemia and resistance to reducing body mass are two characteristics of typical obesity ( 2, 3, 85 ).
Conclusions
The discovery of leptin has provided new insight into how to control obesity. The altered expression of leptin and its receptor leads to leptin resistance, which plays a critical role in obesity-related complications ( 3, 4 ).
Author Contributions
MO, ES-M, and ERI designed, wrote and supervised the manuscript. SS, ME, and SA wrote the manuscript. AJS and TG critically revised the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work is part of the collaboration between the Department of Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia, and Computational Bioscience Research Center (CBRC) at King Abdullah University of Science and Technology (KAUST).
Why is leptin used in obesity?
Leptin and Obesity: Leptin hormone was initially used for the treatment of obesity because of its capability to effectively reduce food intake and body weight. Recent studies have shown that obese individuals have been found to have high levels of circulating leptin.
Why is leptin resistance important?
It is, therefore, important to understand the molecular mechanism of leptin resistance to know its importance as an effective treatment for obesity. Leptin has to cross the blood brain barrier to reach the hypothalamus and exert its anorexigenic effects.
What is a peptide hormone that is produced by fat cells?
Leptin resistance in obesity. Leptin is a polypeptide hormone produced by adipocytes (fat cells) in the body in proportion to the triglyceride content. The hormone binds to and activates the long form of its receptor (LERP-B) in the brain, decreases food intake and increases energy expenditure. A large body of experimental data has shown ...
Why is leptin important for reproduction?
Therefore, the action of leptin is necessary for energy stores to be sensed in the central nervous system, moreover, is essential for reproduction and homeostasis. In addition to this, the altered physiology associated with low-leptin states is reversed effectively with leptin replacement.
Why do fat cells lose fat?
However, when people diet, the fat cells lose some fat because they eat less, which decreased the production of leptin. As a result, the leptin level goes below the leptin threshold and the brain senses starvation 3.
Is leptin resistance an anorexigenic effect?
The inability of this circulating leptin to exert its anorexigenic effects in obese individuals shows that there is a lack of clinical utility of leptin in obesity. This is defined as leptin resistance. Although, the phenomenon of leptin resistance has still not been adequately characterized.
Does leptin help obesity?
Although, the mechanism of leptin transportation across the blood-brain barrier is unclear and prevents the clinical application of leptin for treating obesity. New strategies have been developed in recent years to recover the response to leptin in obesity 1.
What is leptin therapy?
The clinical studies testing leptin therapy for lipodystrophy conducted by the NIDDK Intramural Research Program—and used as the primary scientific basis for FDA approval—required numerous collaborators and spawned new collaborations. Leading this effort was Dr. Phillip Gorden, a former NIDDK Director who returned to the laboratory to continue his research. Because the leptin used in the research was manufactured by industry, the Intramural Research Program and the NIDDK Technology Advancement Office worked with industry to obtain the leptin needed for the studies. In addition, because lipodystrophy affects the liver and kidneys, scientists in the Intramural Research Program with expertise studying those organs were valuable contributors to the studies. Furthermore, collaborators external to the NIDDK have studied the underpinnings of different forms of genetic lipodystrophy; several genes have now been identified. Finally, many of the study participants were evaluated and treated at the NIDDK’s Metabolic Clinical Research Unit, a facility in the NIH Clinical Center that enables scientists to make precise metabolic measurements. It was only through the contributions of all of these collaborators that this translational success story came to fruition.
How is leptin secreted?
Researchers found that leptin is secreted by fat cells and released in proportion to the amount of fat. These observations drastically altered the prevailing view of normal fat tissue as simply a metabolically passive “fat storehouse.”.
How long does it take for leptin to work?
The studies showed that short-term leptin therapy (3 to 8 months) had dramatic benefits in individuals with lipodystrophy. In one study of females with different forms of lipodystrophy, most of whom also had diabetes, leptin therapy improved blood glucose levels, lowered triglyceride levels, and decreased liver fat content.
Why is the OB mutant mouse obese?
Because the ob mutant mouse was obese, the scientists realized that the normal ob gene—and the hormone it encodes—must contribute to leanness. The landmark discovery of leptin unleashed a wave of new research advances in fat biology and metabolism.
Why do people get obesity?
In most cases, obesity results from a complex interaction among an individual’s genes and the environment. Obese individuals, in fact, usually have very high levels of leptin, probably a consequence of the many fat cells secreting it.
Is leptin FDA approved?
The FDA approval of leptin for generalized lipodystrophy is a culmination of decades of research—NIDDK-supported basic research that led to the discovery of leptin, as well as clinical research conducted by scientists in the NIDDK Intramural Research Program and their collaborators testing leptin in people.
Does leptin help with lipodystrophy?
Of note, leptin treatment helps people with lipodystrophy follow a healthful diet. Without leptin, they are always hungry; leptin treatment dramatically reduces their appetite and thus also decreases their food intake. Leptin is the first approved therapy that is indicated for people with generalized lipodystrophy.
Why is leptin resistance important?
Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood-brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions.
Is leptin a hormone?
Abstract. Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin.
Does leptin help obesity?
The mechanisms involved in leptin transportation across the blood-brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity.
Is leptin resistance an anorexigenic effect?
The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized.
Why is leptin important?
"We know that leptin is very important in keeping the immune system happy and that chronic inflammation occurs in the face of inadequate leptin signaling, and that's part of cardiovascular disease .".
Why does leptin go up?
Leptin levels can keep going higher as people get fatter. "We all have a leptin floor; the problem is, we don't have a leptin ceiling," Lustig says. "In leptin resistance, your leptin is high, which means you're fat, but your brain can't see it. In other words, your brain is starved, while your body is obese.
What does Lustig do to help with insulin resistance?
Lustig advises them to reduce resistance to insulin (a hormone that controls blood sugar) and to bring down high levels of triglycerides (a blood lipid). “Insulin resistance generates leptin resistance. The practical advice is: Get your insulin down,” Lustig says.
What nerve is responsible for bringing leptin levels back up?
Then several processes begin within the body to drive leptin levels back up. One includes stimulation of the vagus nerve, which runs between the brain and the abdomen. "The vagus nerve is your energy storage nerve," Lustig says. "Now the vagus nerve is turned on, so you get hungrier.
What is the hormone that causes obesity called?
The truth about the hormone leptin and obesity. It's been called the " obesity hormone" or "fat hormone" -- but also the "starvation hormone.". When scientists discovered leptin in 1994, excitement arose about its potential as a blockbuster weight loss treatment. Even today, the Internet is loaded with sites that sell leptin supplements.
What happens to leptin when you eat less?
But when people diet, they eat less and their fat cells lose some fat, which then decreases the amount of leptin produced. "Let's say you starve, let's say you have decreased energy intake, let's say you lose weight," Lustig says. "Now your leptin level goes below your personal leptin threshold. When it does that, your brain senses starvation.
What is the term for the pancreas producing large amounts of insulin?
That phenomenon is called ‘leptin resistance,'" says Lustig, who has done research on the subject. Leptin resistance is similar to insulin resistance in type 2 diabetes, in which the pancreas produces large amounts of insulin, but the body doesn't respond to it properly.
Does luteinizing hormone increase pulse frequency?
Leptin treatment resulted in increased mean luteinizing hormone (LH) levels and LH pulse frequency, as well as in increased levels of estrogen, IGF1, IGF-BP3, and thyroxine, all of which have positive impacts on bone health [28].
Does leptin help with infertility?
Ob / ob mice lacking leptin as a signal of energy stores are infertile. Leptin treatment reverses infertility in ob / ob mice and accelerates the onset of puberty in normal mice. During starvation, when endogenous leptin levels in mice are low, exogenous leptin maintains LH release and estrous cycle periodicity ( Hileman et al., 2000 ). In humans, the age of menarche is inversely related to serum leptin concentrations ( Matkovic et al., 1997 ). Humans with LEP gene defects have hypothalamic hypogonadism and remain prepubertal. Leptin therapy in these subjects increases gonadotropin secretion and the progression through puberty ( Farooqi and O׳Rahilly, 2005 ). Overall, these observations suggest that leptin is a coordinating signal to the central nervous system that energy stores are sufficient to support the higher energy needs associated with reproduction.
Does leptin reduce hepatic cholesterol?
Leptin treatment administered to ethanol intoxicated mice resulted in significant lowering of hepatic and plasma cholesterol formation. Emerging data now indicates that leptin may be an important regulator of RCT.125 Considering that adipose tissue is a major cholesterol storage depot in the body, 126 depletion of TG by leptin necessitates transport of excess cholesterol to the liver, for elimination via bile. 113 Furthermore, leptin has shown to increase the activity of CYP7A1, a rate-limiting enzyme involved in the conversion of cholesterol into bile. 125 In our previous study, we found leptin administration results in the significant decrease of CES activity, whereas CEH activity was found significantly upregulated in ethanol fed mice, compared to ethanol alone fed mice. 60 Furthermore, we also observed that increased hepatic HMG-CoA reductase activity, and elevated hepatic SREBP-2 protein expression in alcohol fed mice was significantly decreased, following treatment with leptin, implementing the regulatory role of leptin in cholesterol metabolism. 60 Considering that leptin promotes hepatic uptake of plasma cholesterol, 127 partly due to upregulation of scavenger receptor-BI (SR-BI), 125 an increased flux of cholesterol into the liver would provide a mechanistic explanation for the observed decrease in HMG-CoA reductase activity in the liver of alcohol fed mice, after leptin administration. It is also important to note that hepatocytes express leptin receptors 118,128 that mediate insulin like signaling. 118 It has also been shown, in primary hepatocyte cultures, that leptin enhances the inhibitory effects of insulin on glycogenolysis and hepatic glucose production. 128 Moreover, in hepatocytes, insulin treatment has shown to downregulate CYP7A1, while upregulating HMG-CoA reductase. 108,115,125 Thus, exogenous leptin administration may indirectly downregulate cholesterol synthesis through insulin-mediated action. Van Patten et al. have shown evidence that leptin administration to mice resulted in a marked decrease of both BA pool size and hydrophobicity, accompanied by a pronounced decrease in cholesterol absorption. 114 It is postulated that leptin induces the catabolism of cholesterol in the liver, thus reducing the plasma cholesterol concentration, which further confirmed, with other findings, that leptin enhances the activity of CYP7A1 and stimulates BA production. 124 Thus, administration of exogenous leptin markedly reduced alcohol-induced hepatic hypercholesterolemia by virtue of decreased synthesis and increased catabolism of cholesterol, and could be a new potential therapeutic target for the management of alcohol induced hepatic hypercholesterolemia ( Figure 15.2 ).
Is leptin 455 rare?
Despite being extremely rare, leptin deficiency 455 and leptin receptor defects 456 in humans are quite illustrative of the physiologic importance of this hormone. For example, serum leptin levels in humans are generally proportional to adipose mass. 187,457 Thus, the vast majority of obese humans may be considered to be leptin-resistant rather than leptin deficient. 64,186,458 Despite rapid increases in our understanding of obesity and leptin action, the molecular basis of leptin resistance remains poorly understood.
Does leptin help with weight loss?
Leptin -deficient children and adults benefit from subcutaneous injection of leptin, resulting in weight loss, mainly of fat mass, with a major effect on reducing food intake and on other dysfunctions including immunity as described previously [54]. A detailed microanalysis of eating behavior of three leptin-deficient adults before and after leptin treatment revealed reduced overall food consumption, a slower rate of eating and diminished duration of eating of every meal in the three subjects after leptin therapy. This study supports a role of leptin in influencing the motivation to eat before each meal [56]. In a separate study, hormonal and metabolic changes were evaluated before and after leptin treatment [55]. Leptin treatment was able to induce aspects of puberty even in adults, as illustrated by the effect of leptin treatment in one 27-year-old adult male with hypogonadism [55]. In two women between 35–40 years, leptin treatment led to regular menstrual periods and hormonal peaks of progesterone evoking a pattern of ovulation. Although cortisol deficiency was not initially found in leptin-deficient patients, eight months of leptin treatment modified the pulsatility of cortisol with a greater morning rise in cortisol. Leptin could have a previously unsuspected impact on human hypothalamic–pituitary–adrenal function in humans. Metabolic parameters of leptin-deficient patients improved in parallel with weight loss.
Does leptin help with insulin resistance?
Leptin improves insulin sensitivity directly and independently of its effects on food intake and body weight. In rodents, insulin and glucose are reduced shortly after the initiation of leptin treatment, before significant reductions in body fat content are observed. With long-term leptin administration resulting in weight loss, insulin and glucose are reduced to a greater extent than in pair-fed controls. Intracerebroventricular leptin acutely enhances whole body glucose uptake in mice, suggesting that leptin influences insulin sensitivity through central mechanisms. Leptin therapy also reverses insulin resistance and diabetes in two different transgenic models of lipodystrophy through mechanisms not related to reductions in food intake.