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Obesity therapy: altering the energy intake-and-expenditure balance sheet

Key Points

  • Obesity is a chronic disorder of energy imbalance, whereby a long-term excess of energy intake over expenditure leads to the storage of that excess energy as fat. Pharmacological approaches to the management of obesity include altering the balance between energy intake and expenditure and/or altering the partitioning of nutrients between fat and lean tissue.

  • A reduction in absorbed energy can be achieved by altering the amount and type of food ingested or by interference with its absorption. This could be achieved by amplifying the effects of natural anorexigenic signals. These include the adipocyte-derived hormone leptin, as well as the hypothalamic melanocortins that act downstream of leptin. A wide range of other neuropeptides are now considered to be involved in the control of appetite, and all are potential therapeutic targets.

  • Reducing food intake can also be achieved by interfering with natural orexigenic signals. These include neuropeptide Y, melanin-concentrating hormone, and the recently described stomach-derived hormone ghrelin.

  • Pharmacotherapy targeted at molecular pathways that regulate adaptive thermogenesis provides a plausible means of producing a sustained and safe method of increasing total energy expenditure.

  • Increased expression of novel transcription factors, co-activators and translational regulators, such as PGC1 (peroxisome proliferator-activated receptor-γ co-activator 1), FOXC2 (forkhead box C2) and EIF4EBP1 (eukaryotic-translation-initiation-factor-4E binding protein 1), might promote the development of mitochondrial-rich brown adipocytes in white-adipose-tissue depots.

  • Tissue-specific overexpression of UCP3 (uncoupling protein 3) in skeletal muscle represents a potentially interesting means of preventing diet-induced obesity.

  • Beneficial metabolic effects might be expected from agents that inhibit the accumulation of fat mass relative to lean mass.

  • Inhibitors of peroxisome proliferator-activated receptor-γ (PPARγ) or retinoid X receptor-α (RXRα) function could prevent the differentiation of pre-adipocytes to mature fat cells, therefore limiting adipose-tissue mass.

Abstract

Obesity is associated with numerous health complications, which range from non-fatal debilitating conditions such as osteoarthritis, to life-threatening chronic diseases such as coronary heart disease, diabetes and certain cancers. The psychological consequences of obesity can range from lowered self-esteem to clinical depression. Despite the high prevalence of obesity and the many advances in our understanding of how it develops, current therapies have persistently failed to achieve long-term success. This review focuses on how fat mass can be reduced by altering the balance between energy intake and expenditure.

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Figure 1: Leptin and the regulation of adipose-tissue mass.
Figure 2: Schematic representation of the hypothamalic nuclei.
Figure 3: Proposed mechanism of mammalian adaptive thermogenesis.
Figure 4: Proposed cellular effects of PGC1 expression.
Figure 5: Transcriptional activation through the PPARγ–RXRα heterodimer is crucially important in adipogenesis.

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Correspondence to Stephen O'Rahilly.

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DATABASES

LocusLink

β3-adrenoceptor (human)

β3-adrenoceptor (mouse)

AGRP

BDNF

Bdnf

CART

Cart

CB1 cannabinoid receptor

CCK

CCK1 receptor

CHRM3

Chrm3

Cnr1

CNTF

COX II

COX IV

CRF

CRF1 receptor

CRF2 receptor

Dgat

EIF4E

EIF4EBP1

Eif4ebp1

ERα

Foxc2

ghrelin

GHSR

GLP1 receptor

GLUT4

GPR10

HMGIC

Hmgic

HSD11B1

Hsl

5-HT2C receptor

IL-6

Il-6

insulin

leptin

leptin receptor

MC3 receptor

MC4 receptor

Mc3r

Mc4r

MCH

Mch

MCHR1

MCHR2

melanocortin receptors

muscarinic acetylcholine receptors

neuromedin U

neuromedin U receptor 2

NPY

Npy

NPY receptors

Npy1r

Npy2r

NRF1

NRF2

orexin receptors

orexins

perilipin

PGC1

Pgc1

PKA

POMC

PPARα

PPARγ

proglucagon

prolactin-releasing peptide

Ptp1b

RARα

RXRα

TFAM

TRβ

UCP1

Ucp1

UCP2

Ucp2

UCP3

Ucp3

urocortin

Y1 receptor (human)

Y1 receptor (mouse)

Y2 receptor (mouse)

Y5 receptor (human)

Y5 receptor (mouse)

Medscape DrugInfo

orlistat

OMIM

diabetes mellitus

osteoarthritis

sleep apnoea

LINKS

Regeneron Pharmaceuticals

Glossary

WHITE ADIPOSE TISSUE

(WAT). Fat tissue that contains predominantly 'white' adipocytes — cells that specialize in the storage of calorific energy as triglycerides, and its release as free fatty acids in response to changing energy demands.

DYSLIPIDAEMIA

Perturbations in plasma lipid and lipoprotein levels — for example, raised total and/or low-density lipoprotein cholesterol, reduced circulating levels of high-density lipoprotein cholesterol and elevated triglyceride levels — which might be associated with an increased risk of cardiovascular disease.

HYPERPHAGIA

An increased desire to eat.

ARCUATE NUCLEUS

The arc-shaped nucleus at the base of the hypothalamus.

SEROTONERGIC AGONIST

A compound that mimics the actions of serotonin.

OREXIGENIC

Causing an increase in food intake.

ANOREXIGENIC

Causing a reduction in food intake.

CHOLINERGIC

Of the synapses or nerve fibres that liberate acetylcholine.

BROWN ADIPOSE TISSUE

(BAT). Fat tissue that contains predominantly 'brown' adipocytes — cells that have abundant mitochondria (which gives the tissue a brown hue on macroscopic examination) and are specialized in the dissipation of energy through the generation of heat.

PHAEOCHROMOCYTOMA

A catecholamine-secreting tumour that arises from chromaffin cells, usually of the adrenal medulla.

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Crowley, V., Yeo, G. & O'Rahilly, S. Obesity therapy: altering the energy intake-and-expenditure balance sheet. Nat Rev Drug Discov 1, 276–286 (2002). https://doi.org/10.1038/nrd770

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