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Neurotrophic factor control of satiety and body weight

Key Points

  • Brain-derived neurotrophic factor (BDNF) has an important role in the control of energy balance in addition to its roles in neuronal survival and development. Mutations in the gene encoding BDNF or its receptor tropomyosin receptor kinase B (TrkB) lead to marked overeating and severe obesity in both mice and humans.

  • Nutritional state, glucose and anorexigenic hormones, such as leptin and melanocortin, have been found to regulate BDNF gene expression in some known appetite-regulating brain regions such as the ventromedial hypothalamus and dorsal vagal complex, indicating that BDNF actively participates in the control of satiety.

  • It is likely that multiple brain regions mediate the effect of BDNF on energy balance. These brain regions include the arcuate nucleus of the hypothalamus, paraventricular hypothalamus, ventromedial hypothalamus and dorsal vagal complex.

  • The paraventricular hypothalamus is a key structure that produces BDNF to control energy balance. BDNF neurons in the anterior part of this nucleus inhibit food intake and stimulate locomotor activity, whereas BDNF neurons in the medial and posterior parts of the nucleus drive adaptive thermogenesis by polysynaptically projecting to brown adipose tissues.

  • Administration of recombinant ciliary neurotrophic factor (CNTF) can overcome leptin resistance to suppress the appetite and to induce lasting weight loss in obese rodents and humans.

  • CNTF probably reduces obesity-related phenotypes by regulating gene expression in neurons of the arcuate nucleus and by stimulating adult neurogenesis in the hypothalamus.

Abstract

Energy balance — that is, the relationship between energy intake and energy expenditure — is regulated by a complex interplay of hormones, brain circuits and peripheral tissues. Leptin is an adipocyte-derived cytokine that suppresses appetite and increases energy expenditure. Ironically, obese individuals have high levels of plasma leptin and are resistant to leptin treatment. Neurotrophic factors, particularly ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF), are also important for the control of body weight. CNTF can overcome leptin resistance in order to reduce body weight, although CNTF and leptin activate similar signalling cascades. Mutations in the gene encoding BDNF lead to insatiable appetite and severe obesity.

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Figure 1: Key central neural circuits in the regulation of energy balance.
Figure 2: Neural circuits mediating the effect of BDNF on energy (food) intake.
Figure 3: Neural circuits mediating the effect of BDNF on energy expenditure.
Figure 4: CNTF signalling pathways.

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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 the grants from US National Institutes of Health to B.X. (DK103335, NS073930 and NS095425).

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Intracerebroventricular infusion

Administration of chemicals or other reagents into the ventricular system of the brain.

Hypomorphic mice

Mutant mice in which the expression of a gene is reduced.

Adaptive thermogenesis

A process by which brown adipose tissues enhance the combustion of fatty acids into heat in response to physiological and environmental stimuli such as cold.

Hedonic feeding

Consuming food to obtain pleasure in the absence of an energy deficit.

Signal peptide

A short peptide of 5–30 amino acids in length at the amino terminus of a newly synthesized protein that is destined for the plasma membrane or to be secreted from the cell.

Amyotrophic lateral sclerosis

A nervous system disease that is often known as Lou Gehrig's disease, which causes muscle weakness and affects physical function.

Cachectic

Having cachexia that is characterized by loss of appetite, loss of weight, muscle atrophy, fatigue and weakness.

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Xu, B., Xie, X. Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci 17, 282–292 (2016). https://doi.org/10.1038/nrn.2016.24

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