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  • Review Article
  • Published:

Genetic approaches to studying energy balance: perception and integration

Nature Reviews Genetics volume 3, pages 589–600 (2002)Cite this article

Key Points

  • The regulation of body weight involves a homeostatic control system in which hormones that circulate in proportion to body fat stores enter the brain, where they act to reduce food intake and increase energy expenditure. Conditions that cause weight loss reduce the level of these hormones, triggering adaptive increases in hunger and energy efficiency that are sustained until lost weight is regained.

  • Three complementary approaches have been used to advance our understanding of the basic biology of this control system:

  • Forward genetics has helped to identify key molecules in normal and abnormal energy homeostasis.

  • Reverse genetics has helped to clarify the function of these molecules in normal and abnormal energy homeostasis.

  • Physiological studies have generated models for investigating perception and integration of these molecular signals in discrete neuronal pathways.

  • The energy homeostasis system is composed of:

  • Hormones, such as leptin and insulin, that communicate information related to body fat stores to the brain and that coordinate long-term shifts in energy balance to promote weight stability. Other hormones, such as ghrelin and cholecystokinin, facilitate the onset and termination of individual meals.

  • Brain areas, such as the hypothalamic arcuate nucleus, which transduces hormonal input into neurobiological responses that ultimately alter food intake, energy expenditure, endocrine function and glucose metabolism, and such as the lateral hypothalamic area, which receives input from arcuate nucleus neurons and is vital for its transduction into a feeding response. Other areas that are involved in energy homeostasis include the caudate, putamen and nucleus accumbens, which process dopaminergic signals involved in the motivation to eat, and the nucleus of the solitary tract, a hindbrain area that is crucial for processing afferent, meal-related signals that are involved in the perception of satiety.

  • Various genetic and environmental factors can disrupt the function of this homeostatic system and thereby cause obesity. Clarifying the underlying mechanisms is crucial to the development of more effective therapeutic interventions.

Abstract

The homeostatic regulation of adiposity is a physiological concept that originated nearly 70 years ago, the genetic foundations of which have just begun to emerge. A key element of this concept is the existence of one or more humoral mediators, which circulate at levels that reflect body fat stores and which signal through neuronal receptors to elicit appropriate behavioural and metabolic responses over short time periods. Initial insights into adiposity regulation came from the positional cloning of mouse obesity mutations, but the field is now poised to address specific physiological questions using more sophisticated genetic approaches.

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Figure 1: Main hypothalamic regions involved in regulation of food intake in the rat brain.
Figure 2: Control of energy homeostasis by arcuate nucleus neurons.
Figure 3: Effect of endogenous melanocortin antagonists on pigmentation and body weight.
Figure 4: Control of energy balance downstream of the arcuate nucleus.
Figure 5: A potential mechanism for integrating insulin and leptin signalling in hypothalamic neurons.

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Acknowledgements

We thank members of our laboratories for helpful advice and discussion, and M. Baskin for help in preparing the figures. G.S.B. is an Associate Investigator of the Howard Hughes Medical Institute; G.S.B. and M.W.S. are supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pediatrics, Stanford University School of Medicine, Stanford, 94305-5208, California, USA

    Gregory S. Barsh

  2. Department of Genetics, Stanford University School of Medicine, Stanford, 94305-5120, California, USA

    Gregory S. Barsh

  3. Department of Medicine, University of Washington, Seattle, 98195-6420, Washington, USA

    Michael W. Schwartz

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  1. Gregory S. Barsh
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  2. Michael W. Schwartz
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Correspondence to Gregory S. Barsh.

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DATABASES

Jax

diabetes

obese

tubby

Locuslink

Agrp

Cart

Cck

Cckar

Cckbr

Chrm3

D1A

D2

D3

D4

ghrelin

Ghsr

Irs proteins

Jak proteins

Lepr

leptin

Mc1r

Mc3r

Mc4r

MC4R

Mch

α-MSH

Npy

orexin/hypocretin

Pmch

Stat proteins

Stat3

Trh

Tshb

OMIM

obesity

Parkinson disease

Parkinson disease

type II diabetes

FURTHER INFORMATION

Greg Barsh's lab

Michael Schwartz's lab

Glossary

FORWARD GENETICS

A genetic analysis that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis.

REVERSE GENETICS

Genetic analysis that proceeds from genotype to phenotype through gene-manipulation techniques.

ARCUATE NUCLEUS

A region of the hypothalamus that lies at its most ventral portion and surrounds the third ventricle.

LATERAL HYPOTHALAMIC AREA

(LHA). Hypothalamic region, adjacent to the perifornical area, that produces melanin concentrating hormone and hypocretin/orexin. Lesions of the LHA cause decreased feeding.

NEUROPEPTIDES

Secreted peptides produced by neurons in the brain or spinal cord that are used for cell–cell communication, often as neurotransmitters.

PARACRINE

A form of cell–cell communication that depends on a secreted substance that acts over a short distance and does not enter the circulation.

INVERSE AGONIST

A ligand for a G-protein-coupled receptor that, on receptor binding, decreases the affinity of the ligand–receptor complex for the Gα protein subunit, thereby decreasing receptor activity.

HYPERPHAGIA

Increased feeding.

ANORECTIC

The quality of inhibiting food intake.

OREXIGENIC

The quality of stimulating food intake.

AFFERENT NEURON

A neuron that provides input, usually from axonal projections, to other neurons or brain regions.

SYMPATHETIC NERVOUS SYSTEM

The division of the autonomic nervous system that stimulates heart rate, blood pressure and heat production.

THERMOGENESIS

The production of heat that occurs when the body burns calories, such as during exercise.

GONADOTROPHIC AXIS

The system whereby the hypothalamus causes release of hormones from the pituitary gland that control reproductive function.

SOMATOTROPHIC AXIS

The system by which the hypothalamus causes release of growth hormone from the pituitary gland.

ADRENAL GLAND

An organ above the kidney that synthesizes certain steroid hormones and releases adrenaline. The portion of the adrenal gland that synthesizes cortisol (corticosterone in rodents) is stimulated by adrenocorticotrophic hormone released from the pituitary gland.

THYROXINE

The main circulating hormone produced by the thyroid gland that stimulates metabolic rate.

CRE–LOX P

A site-specific recombination system. Two short DNA sequences (lox sites) are engineered to flank the target DNA. Activation of the Cre-recombinase enzyme catalyses recombination between the lox sites, leading to excision of the intervening sequence.

STRIATUM

The portion of the basal ganglia that includes the caudate nucleus, putamen and nucleus accumbens.

BASAL GANGLIA

A group of interconnected nuclei in the forebrain and midbrain that includes the striatum (putamen and caudate nucleus), globus pallidus, subthalamic nucleus, ventral tegmental area and substantia nigra.

DOPAMINE

An important neurotransmitter produced by the substantia nigra.

SUBSTANTIA NIGRA

A region of the ventral midbrain that contains pigment and sends afferent dopamine-releasing neurons to the striatum.

CATECHOLAMINE

A neurotransmitter that is derived from tyrosine, such as dopamine, adrenaline or noradrenaline.

APHAGIA

Failure to eat.

VENTRAL TEGMENTAL AREA

A region of the ventral midbrain that sends afferent dopamine-releasing neurons to the nucleus accumbens.

TRANSNEURONAL TRACING

An experimental approach for mapping neuronal circuits.

HYPERPOLARIZATION

A decrease in the electrical potential across the plasma membrane from its resting value, usually associated with reduced neuronal firing.

DAUER

Juvenile nematode in which development is arrested during unsuitable conditions and resumes when conditions improve.

TONIC SUPPRESSION

The steady-state inhibition of a process that is regulated physiologically by disinhibition.

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Barsh, G., Schwartz, M. Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 3, 589–600 (2002). https://doi.org/10.1038/nrg862

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