Monogenic Obesity

Initial knowledge on the genetic involvement in monogenic obesity was derived from large-scale linkage analysis in obese mice carrying naturally occurring mutations. These analyses have pointed to disease-related loci and have identified the majority of gene mutations leading to monogenic obesity in mice (3). In particular, the genetic characterization of naturally occurring obese animal models, such as ob/ob, db/db, fat and tubby mice, led to the discovery of recessive mutations in the genes encoding leptin (Lep or ob), leptin receptor (Lepr or db), carboxypeptidase E (Cpe, or fat), and tubby (Tub) (5,6). Furthermore, the latest murine obesity gene map identified 248 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes affecting body weight and adiposity (7). Transfer of this knowledge to clinical cases has confirmed the role of the above genes in human monogenic obesity and uncovered the critical role of the leptin/melanocortin pathway in the regulation of energy homeostasis (8). Briefly, this hypothalamic pathway is activated following the systemic release of leptin and its subsequent interaction with the leptin receptor located on the surface of neurons of the arcuate nucleus of the hypothalamus. The downstream signals that regulate energy homeostasis are then propagated via proopiomelanocorin (POMC), cocaine-and amphitamine-related transcript (CART) and the melanocortin system (9,10). While POMC/CART neurons synthesize the anorectic peptide a-melanocyte-stimulating hormone (a-MSH), a separate group of neurons express the orexigenic neuropeptide Y (NPY) and the agouti-related protein, which acts as a potent inhibitor of melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R).

To date, mutations in 11 different genes (Table 1), including LEP, LEPR, POMC, and proconvertase 1 (PCI), have been linked to obesity, in nearly 200 patients (7,30). Patients with monogenic obesity have extremely severe phenotypes that present in childhood and are often associated with additional behavioral, developmental, and endocrine disorders (31). MC4R-linked obesity represents the most prevalent form of

Table 1

Genes Implicated in Monogenic Obesity

Table 1

Genes Implicated in Monogenic Obesity

Gene

Gene symbol

Locus

Mode of transmission

Obesity

Reference

Leptin

LEP

7q31.3

Recessive

Severe, from first

11-

13

days of life

Leptin receptor

LEPR

1q31

Recessive

Severe, from first

14,

15

days of life

Proopiomelano

POMC

2p23.3

Recessive

Severe, from first

16,

17

cortin

month of life

Proconvertase 1

PC1

5q15—q21

Recessive

Considerable, from

18

first month of life

Melanocortin-4-

MC4R

18q22

Dominant

Variable severity,

19-

22

receptor

early onset

Single-minded

SIM1

6q16.3—q21

Dominant

Severe, from

23

homolog 1

childhood

Neurotropic

NTRK2

9q22.1

Dominant

Severe, from first

24

tyrosine kinase

months of life

receptor type 2

Corticotropin-re-

CRHR1

17q12—q22

Dominant

Severe, early onset

25

leasing hor-

mone receptor 1

Corticotropin-re-

CRHR2

7p14.3

Not known Not known

25

leasing hor-

mone receptor 2

G-protein-coupled

GPR24

22q13.3

Dominant Severe, early onset

26

receptor 24

Melanocortin-3-

MC3R

20q13.2

Dominant

Severe, early onset

27-

-29

receptor receptor monogenic obesity identified to date, representing ~2-3% of childhood and adult obesity (30,32,33). MC4R is a G-protein-coupled receptor with seven transmembrane domains that plays an important role in controlling weight homeostasis (10). MC4R knockout mice develop morbid obesity and increased linear growth, whereas heterozygous mice are also obese but with a varying degree of severity (34). Investigations in the molecular mechanisms by which loss of function mutations in MC4R cause obesity have suggested a number of functional anomalies, including abnormal MC4R membrane expression, a defect in agonist response, and disruption in the intracellular transport of the protein (35). Other single gene mutations leading to obesity involve single-minded homolog 1 (SIM1), melanocortin receptor 3 (MC3R), and neurotrophic tyrosine kinase receptor type 2 (TRKB/NTRK2) (23,24,27).

The major goal of the extensive ongoing research is the development of therapies targeting monogenic obesity, in order to ameliorate the metabolic status of obese individuals. Leptin therapy, by subcutaneous injection of leptin in children and adults deficient in this adipokine, markedly reduced their body weight, having a major effect on reducing food intake and on other dysfunctions, including immunity (36). Although treatments are not available yet for cases of LEPR, POMC-, PC1-, SIM1-, MC4R-, and TRKB-linked obesity, preliminary studies suggest that targeted therapies could be possible to develop (37).

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