Being overweight and fit can seem something of a paradox. But a growing body of research is suggesting that this may be possible. However, while evidence points towards this scenario, researchers—and heart charities—remain keen to ensure such findings are not misinterpreted and not viewed as a license for people to be contentedly overweight, sedentary, yet believe they may still be healthy and fit too.
New research from the University of Leeds, centred on a role for endothelial insulin-like growth factor 1 (IGF-1) signalling in obesity, is the latest to explore the ‘fat but fit’ paradox—where some overweight people have a seemingly healthy metabolism. They suggest it may be explained by a good blood supply to fat cells and that improving blood supply to fat could help prevent heart disease. Their study focused on the relationship between white adipose tissue (WAT) expansion and neovascularization becoming uncoupled, leading to inadequate perfusion of adipose tissue. Under these circumstances, the secretory profile of adipocytes becomes unfavourable and pro-atherosclerotic. While obesity-induced perturbations of insulin signalling have been extensively studied, a role for endothelial IGF-1 signalling in obesity is only beginning to emerge.
The Leeds team hypothesized that reducing endothelial IGF-1R expression affects adipose tissue remodelling as a result of communication between endothelial cells and adipocytes. They demonstrated that removal of this receptor in cells lining the inside of blood vessels of mice fed a high-fat diet encouraged the growth of new blood vessels into fat. This was followed by beneficial changes to the fat, which they say may offer protection against heart and circulatory diseases in the long term.
Researchers developed a mouse with inducible endothelial-specific IGF-1R deficiency (ECIGF-1RKD). In the context of diet-induced obesity, ECIGF-1RKD mice were more insulin sensitive and had an anti-atherosclerotic metabolic profile (Figure 1).
Adipose vascularity—mouse adipose tissue showing adipocytes in green (stained with LipidTOX) and vessels in red (Stained with Isolectin B4).
Whole body metabolic assessment using CLAMS-HC revealed an increase in their energy expenditure. They showed favourable changes specific to the WAT, with increased uncoupling protein-1 and vascular endothelial growth factor expression, enhanced endothelial sprouting and greater vascularization (Figure 2). The mechanisms underpinning the specific effect of ECIGF-1RKD on WAT were explored in detail and time course experiments revealed an increase in vascularity preceded the increase in browning.
Adipose neovascularization—human adipose tissue embedded in a fibrin matrix exhibits endothelial sprouting.
Lineage tracing experiments using mTmG labelling eliminated the possibility that ECIGF-1RKD endothelial cells were directly differentiating into brown/brite adipocytes. In vitro treatment of adipocytes with conditioned media from isolated ECIGF-1RKD endothelial cells revealed an altered secretome, which caused browning of white adipocytes in culture.
They believe that blood vessels in fat release bioactive chemicals, which encourage the fat cells to ‘brown’. Brown fat burns calories to generate heat, helps to control blood sugar, blood pressure and cholesterol levels, and protects against the furring of arteries.
Dr Natalie Haywood, Postdoctoral Research Fellow at the University of Leeds, explained: ‘We generated a mouse with endothelial specific IGF-1R knock down and after high fat feeding, we saw that the mice were metabolically healthier and had “healthier fat”’. ‘In our mouse model, the transgenic mice with increased fat vascularity are metabolically healthier than their control littermates. We have patient samples and can see in patients with diabetes they have “unhealthier” fat which has reduced capacity for neovascularisation’.
However, the team has not measured ‘fitness’ markers and fat vascularity in humans directly and is still further probing the mechanism behind the role that IGF-1R plays in the growth of new blood vessels. ‘We are in the process of analysing human samples’, she added. ‘Currently we know that in our samples from patients with diabetes, their fat is similar to our control mice. We also know that their endothelial cells behave differently’. But the broader implications of the findings are that the endothelium communicates with other organs and this communication can be manipulated.
In conclusion the team state: ‘The enhanced WAT angiogenesis and favourable anti-atherosclerotic profile seen in ECIGF-1RKD mice are the result of an altered endothelial secretome. The secretome, its production in the context of IGF-1R depletion, and its action on WAT provide potential novel therapeutic strategies to combat the negative metabolic and atherosclerotic consequences of diet-induced obesity’.
The next stage of the research will see the team probing the cellular mechanism of both the endothelial and adipocytes and to identify the healthy bioactive signals released by blood vessels to potentially harness them to combat heart and circulatory disease in obesity. ‘We also want to correlate the data from the mouse model with our patient samples’, said Dr Haywood.
However, they also acknowledge that any potential drug discovery or therapy resulting from the findings is ‘a long way off’.
‘Potentially at this stage, we could hypothesise that we could either design a small molecule to mimic the changed secretome of the endothelial cells which cause beneficial changes to the adipocytes. Or we could develop a substance that mimics the effect of reducing IGF-1R expression in the endothelial cells and it’s downstream effect within the endothelial cell’.
While pointing out it is a myth that you can be overweight and completely healthy, Dr Haywood said there may be some truth to the ‘fat but fit’ paradox. ‘People with better blood supply to their fat may be more metabolically healthy and could be protected against heart and circulatory diseases’, she continued.
‘However, it is important to stress the key to curing and preventing obesity is a healthy diet and active lifestyle. In the future if a “pill” was developed it does not mean that people can eat whatever they want and have a sedentary lifestyle’.
Findings from the research, funded by the British Heart Foundation, were presented by Dr Haywood at the American Heart Association Scientific Sessions in Philadelphia in mid-November and were awarded the best UK abstract at the conference.
Conflict of interest: none declared.
