How is leptin related to obesity

Inducing weight loss through significant dietary caloric restriction or bariatric surgery followed by leptin treatment has demonstrated mixed results, as noted earlier, but none clinically significant. The confirmatory study was unfortunately discontinued due to the identification of apparent neutralizing antibodies. The opportunity to impact other common metabolic disorders associated with obesity, specifically T2D, severe insulin resistance, NASH, and perhaps polycystic ovary syndrome as well as possibly T1D Wang et al.

Given leptin's pleotropic activities, careful experimental design will need to separate the weight loss-requiring and weight loss-independent actions of leptin to better aim the therapy at disease states that would be responsive.

With the identification of leptin's effect in severe insulin-resistant normal-weight humans Cochran et al. Notably, much of what we have learned about the activity of leptin in humans, as well as the data supporting the initial approval of recombinant leptin were developed by a critical set of investigator-initiated clinical trials, both completed and ongoing. Fewer trials have evaluated patients with partial lipodystrophy, both non-HIV associated Simha et al.

The next steps for leptin will likely be in the hands of the broader scientific and clinical investigative community to further define its biology and clinical applications. The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Mammalian Genome 4 — IDrugs: the Investigational Drugs Journal 4 41 — Metabolic Syndrome and Related Disorders 5 — Journal of Clinical Endocrinology and Metabolism 90 — Journal of Clinical Investigation — Journal of Investigative Medicine 57 — Drugs 73 — Journal of Clinical Endocrinology and Metabolism 89 — Coleman DL Effects of parabiosis of obese with diabetes and normal mice.

Diabetologia 9 — New England Journal of Medicine — Ed E Coleman. Nature Medicine 1 — Genomics 11 — Garg A Lipodystrophies: genetic and acquired body fat disorders. Journal of Clinical Endocrinology and Metabolism 96 — Journal of Biological Chemistry — Journal of the American Medical Association — Journal of Clinical Endocrinology and Metabolism 85 — International Journal of Obesity 26 — American Journal of Clinical Nutrition 77 — Hepatology 41 — Kalra SP Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation.

Peptides 30 — Obesity 21 — American Journal of Physiology. Endocrinology and Metabolism E — E Metabolism 60 — Diabetes 60 — Nature 26 — Journal of Clinical Endocrinology and Metabolism 94 — Cell Metabolism 15 — Nainggolan L Myalept Metreleptin approved for generalized lipodystrophy.

Obesity Surgery 22 — Obesity 17 — Journal of Clinical Endocrinology and Metabolism 81 — Journal of Clinical Endocrinology and Metabolism 87 — PNAS — Journal of Hepatology 59 — World Journal of Gastroenterology 20 — European Journal of Endocrinology — Journal of Clinical Endocrinology and Metabolism 97 — Journal of Clinical Investigation 97 — Obesity 18 21 — Journal of Clinical Endocrinology and Metabolism 83 — About Contact Events News.

Search Search. You and Your Hormones. Students Teachers Patients Browse. Human body. Home Hormones Leptin. Leptin Leptin is a hormone secreted from fat cells that helps to regulate body weight.

The name leptin is derived from the Greek word 'leptos' meaning thin. It is sometimes referred to as the 'Fat Controller'. Alternative names for leptin There are no other names used for the hormone but the gene , which encodes leptin, is known as the 'ob' gene. Many hormones present in the body that upregulate or downregulate the level of leptin. Leptin is upregulated by insulin and cortisol and downregulated by catecholamines.

Leptin also autoregulates its own expression by glucose and fatty acids also influence leptin expression [ 12 ]. Leptin is an important component in the long term regulation of body weight. Recent studies with obese and non- obese humans demonstrated a strong positive correlation of serum leptin concentrations with percentage of body fat.

It appears that as adipocytes increase in size due to accumulation of triglyceride, they synthesize more and more leptin.

Leptin's effects on body weight are mediated through effects on hypothalamic centers that control feeding behavior and hunger, body temperature and energy expenditure [ 13 ]. Studies indicated that in the hypothalamus region, leptin specifically activated STAT3 pathway [ 14 ]. Neuropeptide Y promoted feeding behavior in the body. Absence of the NPY failed to change body weight and feeding in normal mice.

If any of the components missed in pathway then less food intake [ 15 ]. Pathways of the leptin gene have importance in its expression [ 16 ]. Activity of leptin is dependent on its binding with its receptor, known as leptin receptor LEPR. LEPR belong to gp family of cytokine receptor. After the alternative splicing of LEPR, six different isoforms were formed. Out of these six, LEPRb is the important and longest isoform that has the capacity of strong signaling as compared to others.

Defect in leptin signaling cause severe obesity [ 17 ]. First missense mutations which were present in the leptin receptor LEPR were reported. These mutations disrupt LEPR signaling. Mutations associated to human obesity were involved in structural as well as functional relationships within the LEPR [ 18 ].

Leptin is a neurotransmitter expressed in the brain. This neurotransmitter signals to the brain mainly in the hypothalamus that when a person stops to eat for maintaining his Body Mass Index.

It has been observed that lab mice have a polymorphism in the leptin gene. Mutations in this gene prevent to manufacture the functional leptin protein. Due to less leptin expression, mice become morbidly obese. In this case, signal of the leptin is not received by the brain or the hypothalamus.

So due to signal disruption or mutations in the leptin receptor, mice become obese www. A study involves comparison of obese and lean individuals with respect to leptin level.

Experiments included 25 obese and 25 severely lean individuals. Sequence of leptin gene was analyzed by using SSCP, heteroduplex analysis and automated Sanger sequencing.

Result suggested that in Pakistani population leptin gene may not be a major cause for obesity and leanness. Until know six mutations have been reported and these mutations are listed below in Table 1.

Korner et al. Also, no changes were shown in percent fat mass, resting energy expenditure, thyroid hormones, or cortisol levels Those studies examined effects on skeletal muscle and autonomic and neuroendocrine adaptation to mass body maintenance and reproductive hormonal regulation Potential mediators of weight regain, including the cortisol, growth hormone, and thyroid axes were not systematically affected — Synergistic effects of leptin and amylin promote weight loss while preventing the compensatory reduction in energy expenditure associated with weight loss , The combined therapy of leptin and pramlintide an amylin analog results in more weight loss in subjects with obesity than either treatment alone.

This effect seems to be additive rather than synergistic, suggesting that amylin and its analog cannot increase leptin sensitivity , Ravussin et al. Unfortunately, some subjects developing anti-metreleptin antibodies that led to suspending the study.

Later Chan et al. Antibody development in patients with obesity or lipodystrophy was associated with higher leptin concentration, and higher antibody titers were associated with higher leptin concentration Other studies have shown that exercise increases leptin sensitivity in human skeletal muscle , which may provide an alternative to pharmacological sensitizers. Despite the remarkable results of leptin-based therapy on weight loss in genetically predisposed obese subjects mutations in the leptin gene , this approach has a limited or completely absent effect on weight loss in subjects with common obesity, especially in hyperleptinemic patients 3 , Different responses to leptin-based therapy on weight loss in obese subjects in clinical studies may be explained by differences in treated population, study design, and administered therapy leptin type, dosage, etc.

Indeed, further clinical trials are needed to assess the selectivity and effectiveness of leptin-based therapy on weight loss regarding obesity, particularly defined the threshold of endogenous leptin level as a predictive factor for therapy response to determining the dose-response ratio of leptin-based therapy. As previously mentioned, leptin administration combined with a leptin sensitizer is a potential pharmacological strategy for weight loss 5 , 6.

A few studies have examined blocking negative regulators of the leptin signaling pathway, including SOCS3 and PTP1B, to enhance leptin administration effects in individuals with obesity 5 , , Inhibitors of PTP1B, such as thiazolidinedione and trodusquemine, suppress weight gain and decrease food intake and body weight in DIO mice Thus, modulation of endocytosis and the intracellular trafficking of LEP-R 6 may be ways to treat obesity.

Thus, another possible way to improve leptin therapy is to enhance its ability to cross the BBB, potentially fusing it with another molecule to improve uptake by vesicular endocytosis 6. Although leptin reduces food intake and body mass and stimulates energy expenditure, obese subjects that develop leptin resistance did not respond to leptin-based clinical therapies , However, several leptin-sensitizing compounds have been described to influence leptin action and promote beneficial effects in DIO hyperleptinemic mice — Leptin-sensitizing compounds may be divided into two groups Compounds that enhance the anorectic effect of exogenous leptin but minimally affect weight loss, including meta-chlorophenylpiperazine , metformin , and betulinic acid The other group comprises compounds that induce weight loss in obese animals with hyperleptinaemia and restore endogenous leptin signaling, such as glucagon-like peptide-1 and heat shock protein 90 inhibitors , Some of these leptin sensitizers are in clinical use for diabetes therapy, such as amylin and pramlintide, that enhance leptin action, probably increasing IL-6 production in microglia ventromedial hypothalamic nucleus that in turn activates pSTAT3 signaling in LepR neurons , It was found that resveratrol attenuates the expression of leptin in adipocytes, elevates phosphorylation of STAT3 in the hypothalamus, and restores leptin resistance in adult offspring from HF rat mothers attenuating obesity Ozcan and colleagues identified the natural compound celastrol as a potential leptin sensitizer and anti-obesity agent Another natural compound that acts as a potential leptin sensitizer with additional anti-diabetic actions is withaferin A A partial reduction of plasma leptin level by leptin neutralizing antibody in obesity state improved leptin sensitivity and effectively led to weight loss and enhanced insulin sensitivity Despite the impressive leptin sensitizing effects, using celastrol or withaferin A as an anti-obesity drug has some adverse effects — Zhao et al.

Partial leptin reduction has been characterized by returning leptin sensitivity in the hypothalamus, improving insulin sensitivity, and successfully diminishing weight gain The same author suggested that increased leptin sensitivity resulting from partial leptin reduction is a new promising therapeutic tool for treating obesity Another study by Ottaway et al.

Regarding diet-induced obese DIO mice, antagonist improved body weight BW and feeding in lean mice This improvement is related to the decline of expression of Socs3 in the hypothalamus There is an estimation that DIO mice that have hyperleptinemia maintain leptin-feeding inhibition similar to lean mice and oppose an attitude that the stability of DIO in mice is based on resistance to endogenous leptin action 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. The focus of further studies should be identifying new mechanisms of leptin regulation at the whole-body level to design new drugs that reverse leptin resistance. In this regard, understanding the pathogenesis of obesity-related disorders and the regulation of energy homeostasis by leptin should provide new alternatives in obesity treatment.

AJS and TG critically revised the manuscript. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Google Scholar. Curr Opin Endocrinol Diabetes Obes —9. Nutrients Front Endocrinol Lausanne Life Sci — Nature — J Clin Invest — J Biol Chem — Nature —9.

J Clin Endocrinol Metab — Metabolism — Diabetes —5. J Clin Endocrinol Metab —5. Clin Nutr —4. Eur J Endocrinol R59—r Mol Pharmacol —5. PubMed Abstract Google Scholar. Munzberg H, Morrison CD. Structure, Production and Signaling of Leptin. Bazan JF. Biochem Biophys Res Commun — Cell — Fruhbeck G.

Intracellular Signalling Pathways Activated by Leptin. Biochem J — Myers MG Jr. Recent Prog Horm Res — Stellar E. The Physiology of Motivation. Psychol Rev — Nature —2. Hetherington AW RS. J Comp Neurol Brobeck JR. Physiol Rev — Proc Soc Exp Biol Med —4. Ahima RS. J Clin Invest —3. Front Endocrinol Li MD. Yale J Biol Med —7. Diano S. Front Neuroendocrinol — Neuron — Nature —4. J Clin Endocrinol Metab —6. Diabetes — Science —5.

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