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Leptin and brain–adipose crosstalks

Key Points

  • Leptin plays a key role in the neural regulation of adipose tissues

  • The sympathetic nervous system is crucial in regulating leptin production

  • Fasting differentially modulates the sympathetic outflow to different fat pads

  • The pattern of sympathetic innervation varies across fat pads and animal species

  • Manipulating the sympathetic outflow to adipose tissues may be beneficial to the development of novel anti-obesity and anti-diabetes therapies

Abstract

Interactions between the brain and distinct adipose depots have a key role in maintaining energy balance, thereby promoting survival in response to metabolic challenges such as cold exposure and starvation. Recently, there has been renewed interest in the specific central neuronal circuits that regulate adipose depots. Here, we review anatomical, genetic and pharmacological studies on the neural regulation of adipose function, including lipolysis, non-shivering thermogenesis, browning and leptin secretion. In particular, we emphasize the role of leptin-sensitive neurons and the sympathetic nervous system in modulating the activity of brown, white and beige adipose tissues. We provide an overview of advances in the understanding of the heterogeneity of the brain regulation of adipose tissues and offer a perspective on the challenges and paradoxes that the community is facing regarding the actions of leptin on this system.

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Figure 1: Sympathetic regulation of white, brown and beige adipose tissues.
Figure 2: Sympathetic regulation of leptin production.
Figure 3: Leptin-sensitive neurons regulating adipose depots.
Figure 4: Sympathetic and sensory innervation of adipose tissues.

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Acknowledgements

The authors apologize to all colleagues whose work could not be cited owing to space limitations. This work was supported by US National Institutes of Health grants DK053301, R01 DK088423 and R01 DK100659 to J.K.E. A.C. is a Canadian Diabetes Association postdoctoral fellow.

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Contributions

A.C. wrote the manuscript and prepared the figures. J.K.E., A.C., L.G. and S.L. researched, discussed and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Joel K. Elmquist or Laurent Gautron.

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The authors declare no competing financial interests.

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Glossary

SNS outflow

The release of neurotransmitters derived from sympathetic neurons in peripheral tissues.

Fat mobilization

A process, in response to signals for energy, in which fatty acids are released from triglyceride stores in fat cells and delivered to organs.

Dermomyotome

The epithelial cell layer constituting the dorsal part of the somite lying under the ectoderm. It gives rise to the dorsal dermis and to the skeletal muscle of the myotome.

Bilateral chain

A symmetric chain of sympathetic ganglia located just ventral and lateral to the spinal cord.

Terminal ganglia

Parasympathetic ganglia situated within or close to an innervated organ and the site where preganglionic nerve fibres terminate.

Noradrenaline turnover

A surrogate index of changes in sympathetic activation, based on the assumption that tissue levels of noradrenaline decline at a rate proportional to initial noradrenaline concentrations. Increased noradrenaline turnover implies increased sympathetic activation.

Zeitgeber time

A quantification of time based on the period of a zeitgeber. Under standard light–dark cycles, the time at lights-on is usually defined as zeitgeber time 0 for diurnal organisms, and the time at lights-off is defined as zeitgeber time 12 for nocturnal animals.

β-Blockers

β-Adrenergic blocking agents that prevent the effects of the hormone adrenaline.

Ectopic lipid accumulation

An accumulation of lipids in lean tissues such as kidneys, liver, muscle and heart that results in lipotoxicity and metabolic diseases.

Lipotoxicity

The accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death.

Multilocularity

The appearance of cytoplasmic lipids arranged in numerous small droplets.

Thoracolumbar ganglia

Ganglia arising from the thoracolumbar (T1–L2) regions of the spinal cord.

Fluoro-gold

A fluorescent retrograde axonal tracer.

Thermoneutrality

The state of thermal balance at which an organism does not need to generate heat in order to maintain a normal core temperature.

Pyrexic

Relating to factors that raise body temperature above normal.

Leptin resistance

Reduced sensitivity with respect to the metabolic responses to exogenously administered leptin.

Calorimetry

The process of measuring the amount of energy as heat released, or absorbed, by an organism.

O-GlcNAc transferase

(OGT). An enzyme that catalyses the addition of an N-acetylglucosamine group in O-glycosidic linkage to serine or threonine residues of intracellular proteins.

Hypothermic

A condition that leads to a decrease in body core temperature — be that regulated, accidental or forced — when the body dissipates more heat than it generates.

Anapyrexic

Relating to decreases in body temperature below normal.

Lipopolysaccharide

Large molecules found in the outer membrane of Gram-negative bacteria. They elicit strong immune responses.

Omental

Adipose tissue located in the omentum, a layer of peritoneum that surrounds abdominal organs.

Cachexia

A syndrome characterized by uncontrolled weight loss, muscle atrophy, fatigue and weakness.

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Caron, A., Lee, S., Elmquist, J. et al. Leptin and brain–adipose crosstalks. Nat Rev Neurosci 19, 153–165 (2018). https://doi.org/10.1038/nrn.2018.7

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