Regulation of energy balance by leptin as an adiposity signal and modulator of the reward system

Abstract

Background: Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose-response window.

Scope of review: This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions.

Major conclusions: Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.

Keywords: Body weight; Food intake; Leptin; Reward system.

Figure 1

Leptin's role in the regulation of energy balance via the hypothalamus (A) and the ventral tegmental area (B). The figure focuses on the direct effects of leptin in specific brain regions and on leptin's effects on first order neurons. As described in the text, leptin action in the brainstem and periphery also regulates energy balance. AgRP, agouti-related protein; NPY, neuropeptide Y; POMC, proopiomelanocortin. Created with BioRender.com.

Figure 2

Mechanisms of leptin resistance (in red boxes). ER, endoplasmic reticulum; IKKβ/NFκB, inhibitor of κB kinase β/nuclear factor κB; JAK2, janus kinase 2; LepRb, long isoform of the leptin receptor; PTP1B, protein tyrosine phosphatase 1 B; SHP2, SH2 containing protein tyrosine phosphatase 2; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3. Created with BioRender.com.