Genetic obesity,


Uppsala University's Helgi B Schiöth, Christian Benedict, Pawel Olszewski, Samantha Brooks, and Robert Fredriksson provide new insight into the mechanisms causing obesity

Overeating that is elicited by rewarding and cognitively salient stimuli are dominating factors for the current obesity epidemic. A number of environmental factors, as well as social and other non-eating behaviour such as sleep deprivation and work-overload are associated with obesity, but the underlying mechanisms are often not well understood.

There is a strong genetic component to obesity, and the identification of new genes that are associated with common forms through genome-wide association (GWA) studies have provided new opportunities to understand the underlying mechanisms.

About 32 genes have been identified that are associated with common forms of obesity, most of which do not have a clear functional role that is related to obesity.1Moreover, it is estimated that more than 250 additional common variant loci exist with effects on BMI similar to those 32 that remain to be discovered, and that there exist even larger numbers of loci with smaller effects.

FTO is the gene that has the strongest association, and several studies have shown that common intronic variants in this gene are linked with increased body weight and adiposity. 2Individuals homozygous for a certain FTO allele weigh ~3kg more than those with low-risk alleles. This short report introduces some of the projects and recent highly cited results obtained in this field at the Unit of Functional Pharmacology, Department of Neuroscience at Uppsala University.

Sleep and obesity
Epidemiological data indicates that a reduction in nocturnal sleep time is associated with an increased risk of developing obesity. 3However, the molecular mechanism for how sleep derivation triggers obesity remains elusive. Findings show that one night of sleep deprivation acutely reduces energy expenditure in healthy men, which suggests that sleep contributes to the acute regulation of daytime energy expenditure in humans.4 Nocturnal wakefulness increases morning plasma ghrelin concentrations and nocturnal and daytime circulating concentrations of thyreotropin, cortisol, and norepinephrine, as well as morning postprandial plasma glucose concentrations. Further studies suggest that sleep deprivation has intriguing effects in the reward pathways using fMRI studies.5

Obesity and cognition
Recent neuroimaging studies have revealed that FTO polymorphisms are associated with a reduction in frontal lobe volume 6and increased risk for incident Alzheimer's disease.7 Data indicates that an FTO allele is associated with diminished performance on a verbal fluency task in overweight and obese men but not in lean elderly men (see Fig. 1).8 This finding suggests that the FTO gene exerts a modulating influence on human cognition that is dependent on an individual's body weight. This was the first report showing an association of a common obesity gene variant with cognitive functions in humans.

Functional role of FTO
The FTO gene is widely expressed in the feeding centres of the brain. It is notable that FTO expression is dense in hypothalamic regions, including the arcuate, paraventricular, and dorsomedial nuclei that encompass key genes influencing hunger and satiety, such as NPY, AGRP, POMC and MC4R (see Fig. 2). But the FTO gene is also expressed in a number of other regions of the brain that are not directly related to the hunger signal. The expression mapping suggests that FTO is 'activated' at termination rather than initiation of feeding. Moreover, colocalisation with oxytocin suggests that FTO may be involved in mechanisms that end consummatory activity, thus, those that are closely tied with meal size control and therefore, the amount of ingested energy.9

Several other obesity genes such as the TMEM1810 are also currently being characterised from both functional and genetic perspectives.

Identification of transporters
Over 40 novel human genes have previously been identified for solute carriers (SLCs), a class of ATP independent transporters, as well as a number of other membrane bound proteins such as GPCRs. 11Membrane bound proteins continue to be very important drug targets.12 A number of such targets are being characterised with the aim of evaluating new pharmaceutical avenues with an emphasis on amino acid transportation. The amino acid leucine has previously been shown to induce satiety and reduction of food intake beyond what is explained by its caloric content only. Leucine was also shown to activate specific neurons in a satiety mediating region, the paraventricular nucleus, of the hypothalamus through the mTOR pathway. 13However, the molecular mechanisms underlying this fundamental biological response to leucine is not well understood. We have recently seen that leucine injected animals ate significantly less in the first two hours of refeeding, and that this effect disappeared in a leucine transporter knockout mice. These data suggest that we have identified a transporter that is important for mediating the satiety effect from leucine.

We are also deorphanising a range of other transporters for amino acids. We have characterised an orphan transporter SLC38A7, by expressing the transporter in X. laevis oocytes. Using an uptake assay, we have shown that this transporter has highest transport for the amino acid glutamine as well as weaker transport for alanine (see Fig. 3).14 We also showed that this transport is saturable with time and that the transport is ion-driven with a preference for sodium over lithium and choline. This profile is consistent with a system A transporter and we suggest that these are candidates for the neuronal glutamine uptake in the synapses. Preliminary data also suggests that additional new amino acid transporters have been found.

1Speliostes et al, Nature Genetics 2010
2Frayling et al, Science 2007
3Spiegel et al, Nat Rev Endocrinol, 2009
4Benedict et al, Am J Clin Nutr. 2011
5Benedict et al, submitted
6Ho et al, Proc. Natl. Acad. Sci. 2010
7Keller et al, J Alzheimer's Dis. 2010
8Benedict et al, Neurobiol. Aging, 2011
9Fredriksson et al, Endocrinology, 2008, Olszewski et al, BMC Neuroscience, 2009, Physiol Behav. 2011 and BBRC, 2011
10Almen et al, BMC Med Genet. 2010
11Fredrikson et al, Mol. Pharmacol., 2003, Lagerström and Schiöth, Nature Review Drug Discovery, 2008, Fredriksson et al, Febs letters, 2008, Almen et al, BMC Biol., 2010
12Rask-Andersen et al, Nature Review Drug Discovery, In press
13Cota et al, Science, 2006
14Hägglund et al, J. Biol. Chem., 2011

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