The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) helps to translate 'what you eat' into 'what you are' because it allows dietary fatty acids (PPARγ) ligands to modulate gene transcription.
Treatments for diabetes include PPARγ activators, as they sensitize the body to insulin.
Scientific understanding of PPARγ function has recently been enhanced by a flurry of human and mouse genetic studies, and the characterization of new PPARγ ligands.
This insight has led scientists to propose that modulating PPARγ activity, rather than activating it, might be the most effective strategy for treating metabolic disorders, as this will improve glucose homeostasis while preventing adipogenesis.
The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that is crucial for whole-body energy homeostasis and adipogenesis.
The actions of PPARγ are mediated by two protein isoforms: the widely expressed PPARγ1 and the adipose tissue- restricted PPARγ2.
The activity of PPARγ is governed by the binding of small lipophilic ligands – mainly fatty acids – that are derived from nutrition or metabolism, and the activation of PPARγ leads to adipocyte differentiation and fatty-acid storage.
The modern westernized lifestyle – characterized by a high caloric intake and a lack of physical exercise – exposes people to prolonged chronic levels of fatty-acid-like PPARγ ligands, which, through a feed-forward pathway, often results in obesity.
Obesity is more prevalent in affluent societies, along with associated metabolic diseases such as hyperlipidaemia, insulin resistance, type 2 diabetes and cardiovascular diseases, which constitute a heavy social and economic burden.
It therefore seems ironic that synthetic PPARγ ligands, such as thiazolidinediones (TZDs), are used to treat diabetes because they sensitize the body to insulin; their down side is that they also promote fat accretion, and the long-term consequences of this are unknown.
Moreover, the mechanism by which TZDs act and the reasons why they are effective are still not understood.
It is therefore essential that these pathways be clearly defined to pave the way for better treatments for these metabolic diseases.
Now that recent data have shed more light on the roles of PPARγ, scientists propose that insulin sensitization without the accompanying increase in fat deposition might be possible through the controlled regulation of PPARγ activity.
From an evolutionary perspective, a 'thrifty response' clearly favours survival.
However, caloric restriction, which refers to a dietary regimen that is low in calories without undernutrition, is also known to extend lifespan in species ranging from yeast to non-human primates.
The beneficial effects of caloric restriction have been associated with alterations in metabolism, particularly the insulin/insulin-like growth factor 1 (IGF-1) pathways, and a decreased fat mass.
These pathways converge on the FOXO forkhead transcription factors, which are activated when insulin/IGF-1 signalling decreases and this translates ultimately into increased stress resistance, which is the hallmark of caloric restriction.
The most plausible hypothesis to explain the anti-ageing effects of caloric restriction states that the reduced flow of carbon through the glycolytic pathways slows down the conversion of NAD+ to NADH, which is recognized by neuroendocrine sensors that ultimately reduce the production of growth hormone by the pituitary (and, in turn, IGF-1) and of insulin by the pancreas.
It has been proposed that the sirtuins, which are a family of NAD+-regulated protein deacetylases, have a role in these signalling events.
The importance of insulin/IGF-1 signalling in longevity is supported by the extended lifespan of humans, mice, Caenorhabditis elegans and Drosophila that carry mutations in the insulin/growth hormone/IGF-1/FOXO signalling pathways.
In contrast to caloric restriction, mice with increased fat mass have a shorter lifespan.
It is, at present, unclear how PPARγ interfaces with this signaling pathway, but the fact that PPARγ coordinates adipogenesis and glucose homeostasis leads scientists to speculate that it might also affect longevity.
Collectively, these data indicate that moderate levels of PPARγ activation coordinate an evolutionarily beneficial and adaptive response.
Throughout human evolution, longevity has been improved because efficient energy conservation and storage has allowed survival through periods of food shortages, whereas an enhanced innate immune response combated infections, uncontrolled cell proliferation and cancers.
Our present affluent lifestyle, which exposes us to excessive levels of natural PPARγ activators, throws this tightly regulated system out of balance.
Being born with a 'silver spoon in your mouth' (that is, enjoying an affluent and often sedentary lifestyle) now turns this once favourable energy conservation response into a detrimental one, which contributes to the pathogenesis of lifestyle-associated diseases, such as obesity, type 2 diabetes and atherosclerosis.
This also indicates that modulating (or inhibiting) PPARγ activity, rather than activating it, might be the preferred therapeutic strategy to treat metabolic disorders, in order to improve glucose homeostasis yet prevent adipogenesis.