Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

• Keywords
• Alzheimer´s-like pathology, anorexigenic neuropeptides, antiobesity treatment, neuroprotection,
• MeSH
• Alzheimer Disease drug therapy   metabolism   pathology   prevention & control   MeSH
• Hypothalamus drug effects   metabolism   pathology   MeSH
• Anti-Obesity Agents * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Brain drug effects   metabolism   pathology   MeSH
• Neurodegenerative Diseases drug therapy   metabolism   prevention & control   MeSH
• Neuropeptides * metabolism   pharmacology   therapeutic use   MeSH
• Neuroprotective Agents * pharmacology   therapeutic use   MeSH
• Obesity * drug therapy   metabolism   MeSH
• Eating drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Anti-Obesity Agents * MeSH
• Neuropeptides * MeSH
• Neuroprotective Agents * MeSH

Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.

• Keywords
• Peptide therapeutics, lipidization, structure modification, therapeutic lipopeptides,
• MeSH
• Lipids * chemistry   MeSH
• Peptides * chemistry   therapeutic use   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Lipids * MeSH
• Peptides * MeSH

Prolactin-releasing peptide (PrRP) has been proposed to mediate the central satiating effects of cholecystokinin (CCK) through the vagal CCK1 receptor. PrRP acts as an endogenous ligand of G protein-coupled receptor 10 (GPR10), which is expressed at the highest levels in brain areas related to food intake regulation, e.g., the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS). The NTS and PVN are also significantly activated after peripheral CCK administration. The aim of this study was to determine whether the endogenous PrRP neuronal system in the brain is involved in the central anorexigenic effect of the peripherally administered CCK agonist JMV236 or the CCK1 antagonist devazepide and whether the CCK system is involved in the central anorexigenic effect of the peripherally applied lipidized PrRP analog palm-PrRP31 in fasted lean mice. The effect of devazepide and JMV236 on the anorexigenic effects of palm-PrRP31 as well as devazepide combined with JMV236 and palm-PrRP31 on food intake and Fos cell activation in the PVN and caudal NTS was examined. Our results suggest that the anorexigenic effect of JMV236 is accompanied by activation of PrRP neurons of the NTS in a CCK1 receptor-dependent manner. Moreover, while the anorexigenic effect of palm-PrRP31 was not affected by JMV236, it was partially attenuated by devazepide in fasted mice. The present findings indicate that the exogenously influenced CCK system may be involved in the central anorexigenic effect of peripherally applied palm-PrRP31, which possibly indicates some interaction between the CCK and PrRP neuronal systems.

• MeSH
• Appetite Depressants administration & dosage   MeSH
• Hormone Antagonists administration & dosage   MeSH
• Chemokines, CC drug effects   metabolism   MeSH
• Cholecystokinin metabolism   MeSH
• Devazepide administration & dosage   MeSH
• Prolactin-Releasing Hormone administration & dosage   analogs & derivatives   MeSH
• Injections, Intraperitoneal MeSH
• Injections, Subcutaneous MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Paraventricular Hypothalamic Nucleus drug effects   metabolism   MeSH
• Solitary Nucleus drug effects   metabolism   MeSH
• Fasting MeSH
• Peptide Fragments administration & dosage   MeSH
• Eating drug effects   MeSH
• Proto-Oncogene Proteins c-fos metabolism   MeSH
• Signal Transduction MeSH
• Sincalide administration & dosage   analogs & derivatives   MeSH
• Feeding Behavior drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Appetite Depressants MeSH
• Hormone Antagonists MeSH
• Ccl28 protein, mouse MeSH Browser
• Chemokines, CC MeSH
• Cholecystokinin MeSH
• Devazepide MeSH
• Fos protein, mouse MeSH Browser
• Prolactin-Releasing Hormone MeSH
• JMV 236 MeSH Browser
• palm11-PrRP31 MeSH Browser
• Peptide Fragments MeSH
• Proto-Oncogene Proteins c-fos MeSH
• Sincalide MeSH

Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, γ-glutamic acid at Lys11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders.

• MeSH
• beta-Lactamases metabolism   MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Diet * MeSH
• Prolactin-Releasing Hormone chemistry   metabolism   MeSH
• Binding, Competitive MeSH
• Cricetinae MeSH
• Metabolomics MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Nuclear Magnetic Resonance, Biomolecular MeSH
• Obesity etiology   metabolism   MeSH
• Peptides chemistry   pharmacology   MeSH
• Amino Acid Sequence MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• beta-Lactamases MeSH
• Prolactin-Releasing Hormone MeSH
• Peptides MeSH

OBJECTIVES: Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. RESULTS: Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight and improved metabolic parameters, and attenuated lipogenesis in mice with diet-induced obesity. CONCLUSIONS: Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.

• MeSH
• Energy Metabolism MeSH
• Prolactin-Releasing Hormone analogs & derivatives   pharmacology   MeSH
• Anti-Obesity Agents pharmacology   MeSH
• Lipids chemistry   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity prevention & control   MeSH
• Half-Life MeSH
• Eating MeSH
• Appetite Regulation MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Prolactin-Releasing Hormone MeSH
• Anti-Obesity Agents MeSH
• Lipids MeSH