Leptin resistance and diet-induced obesity: central and peripheral actions of leptin

doi:10.1016/j.metabol.2014.10.015

Metabolism

Volume 64, Issue 1, January 2015, Pages 35-46

https://doi.org/10.1016/j.metabol.2014.10.015 Get rights and content

Abstract

Obesity is a chronic disease that represents one of the most serious global health burdens associated to an excess of body fat resulting from an imbalance between energy intake and expenditure, which is regulated by environmental and genetic interactions. The adipose-derived hormone leptin acts via a specific receptor in the brain to regulate energy balance and body weight, although this protein can also elicit a myriad of actions in peripheral tissues.

Obese individuals, rather than be leptin deficient, have in most cases, high levels of circulating leptin. The failure of these high levels to control body weight suggests the presence of a resistance process to the hormone that could be partly responsible of disturbances on body weight regulation. Furthermore, leptin resistance can impair physiological peripheral functions of leptin such as lipid and carbohydrate metabolism and nutrient intestinal utilization.

The present document summarizes those findings regarding leptin resistance development and the role of this hormone in the development and maintenance of an obese state. Thus, we focused on the effect of the impaired leptin action on adipose tissue, liver, skeletal muscle and intestinal function and the accompanying relationships with diet-induced obesity. The involvement of some inflammatory mediators implicated in the development of obesity and their roles in leptin resistance development are also discussed.

Section snippets

What causes leptin resistance underlying obesity?

Leptin, the product of the ob gene, was identified and cloned from rodent adipose tissue in 1994, where a role in body weight control was described [1]. Leptin was pioneerly considered as an adipose signal mainly implicated in the regulation of the energy balance, as demonstrated in leptin deficient ob/ob mice, in which hyperphagia and obesity are marked features. Many of the actions of leptin are attributable to effects in the brain. Thus, leptin reaches the central nervous system (CNS) by

Inflammatory mediators in obesity and their effects on leptin sensitivity

Obesity is frequently associated with systemic and local inflammation, as well as with elevated circulating leptin levels [24] (Fig. 1). Various inflammatory cytokines are known to induce oxidative stress; while leptin resistance in obesity has been suggested to be initiated by activation of the inflammatory signaling [21]. Previous in vitro and in vivo studies have described that several inflammatory mediators such as C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-alpha

Peripheral actions of leptin and leptin resistance

Leptin is a pleiotropic hormone with a variety of functions within the organism activity in different tissues [9], [10]. Liver and skeletal muscle are the tissues with great metabolic activity and, together with adipose tissue, constitute important targets for leptin regulation of insulin sensitivity as well as glucose and lipid metabolism [10], [58]. Thus, several researches have reported that leptin administration improves insulin functions in normal and diabetic rats [59], [60] and can

Gastric leptin action at small intestinal level: obese vs lean subjects

Nowadays, it is known that leptin is secreted not only by adipose tissue, but also by other tissues such as placenta, fetal tissues, muscle, ovary, kidney and stomach [9], [80]. In the past years, different actions of leptin on the gastrointestinal tract have been described in the scientific literature supporting the consideration of leptin as a gut peptide within a gut–brain loop [81].

Leptin resistance and its relationship with diet-induced obesity (DIO)

Leptin resistance is implicated in the pathogenesis of DIO [107]. High-fat diet consumption triggers central and peripheral leptin resistance as has been extensively demonstrated in rodent models of DIO devoted to study those metabolic disorders related with human obesity. In this sense, hyperleptinemia seems to be a key player in the development of leptin resistance by down-regulating cellular responses to the hormone [108]. However, several controversial outcomes have been reported in this

Summary

Nowadays it is clear that leptin is an adiposity signal to the brain and that leptin resistance in some studies is a primary risk factor associated with obesity. At central level, leptin targets multiple neuronal populations (NPY, POMC, AgRP, etc.) in different hypothalamic regions. These neurons connect with other neurons in the brain forming an orchestrated circuit that also integrates other metabolic signals to control energy intake and expenditure. At peripheral level, among other

Authors’ contributions to manuscript

NS, JB, MJMA and JAM designed the manuscript content; NS and JB wrote the initial paper; MJMA and JAM critically revised the paper; JAM had primary responsibility for final content. All authors read and approved the final manuscript.

Disclosure statement

The authors declare that they have no competing interests.

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Leptin in the 21st CenturyLeptin resistance and diet-induced obesity: central and peripheral actions of leptin

Abstract

Section snippets

What causes leptin resistance underlying obesity?

Inflammatory mediators in obesity and their effects on leptin sensitivity

Peripheral actions of leptin and leptin resistance

Gastric leptin action at small intestinal level: obese vs lean subjects

Leptin resistance and its relationship with diet-induced obesity (DIO)

Summary

Authors’ contributions to manuscript

Disclosure statement

Vitam Horm

Trends Immunol

Cell Metab

Lancet

Metabolism

Physiol Behav

FEBS Lett

Biochem Biophys Res Commun

Life Sci

J Biol Chem

Cell Metab

Trends Endocrinol Metab

Cell Metab

J Biol Chem

J Am Coll Cardiol

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Gastroenterology

Exp Toxicol Pathol

Exp Mol Pathol

Lab Invest

J Nutr

FEBS Lett

Nutrition

FEBS Lett

FEBS Lett

Biochem Biophys Res Commun

J Biol Chem

Positional cloning of the mouse obese gene and its human homologue

Nature

Human blood–brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels

J Clin Invest

Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats

Neuroendocrinology

Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice

Am J Physiol Endocrinol Metab

Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice

J Neurosci

Effects of the obese gene product on body weight regulation in ob/ob mice

Science

Leptin: physiological actions

J Physiol Biochem

Peripheral actions of leptin and its involvement in disease

Nutr Rev

Leptin effect on galactose absorption in mice jejunum

J Physiol Biochem

Leptin regulates sugar and amino acids transport in the human intestinal cell line Caco-2

Acta Physiol (Oxf)

Abnormal regulation of the leptin gene in the pathogenesis of obesity

Proc Natl Acad Sci U S A

Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action

Nat Med

Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

Nat Med

Leptin receptor action and mechanisms of leptin resistance

Cell Mol Life Sci

Molecular and anatomical determinants of central leptin resistance

Nat Neurosci

Hyperleptinemia is associated with parameters of low-grade systemic inflammation and metabolic dysfunction in obese human beings

Front Integr Neurosci

Prevention and reversal of diet-induced leptin resistance with a sugar-free diet despite high fat content

Br J Nutr

Promising new causal explanations for obesity and obesity-related diseases

Biol Res Nurs

Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects

Int J Obes Relat Metab Disord

Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance

J Clin Invest

In vivo and in vitro evidence for the involvement of tumor necrosis factor-alpha in the induction of leptin by lipopolysaccharide

Leptin in the 21st Century
Leptin resistance and diet-induced obesity: central and peripheral actions of leptin