Circulating Protein Helps Fat Cells Resist Weight Loss

MedicalResearch.com Interview with:
Dr. Andrew Whittle,
joint first-author of the paper and a postdoc in the
Prof. Vidal-Puig’s lab at the time the research was conducted.

Medical Research: What is the background for this study?

Dr. Whittle: Antonio Vidal-Puig heads the disease model core of the University of Cambridge Metabolic Research Laboratories at the Wellcome Trust-MRC Institute of Metabolic Science (IMS). His laboratory has a long-standing interest in the mechanisms that regulate how adipose tissue stores, burns or releases energy. The group studies mice that have increased or reduced susceptibility to obesity and its metabolic complications, in order to dissect the molecular pathways that underpin these phenotypes. Their long-term goal is to develop more effective strategies to manipulate the body’s own regulatory pathways, both to reduce obesity itself or limit the negative impact that excess lipids have on other important metabolic organs.

Professor Hideaki Bujo from Toho University Medical Center in Japan has been working for a number of years to understand the role of specific lipoprotein receptors in vascular biology. Specifically he has shown that LR11 is cleaved to release a short soluble for of the protein, sLR11, which can effect changes to vascular smooth muscle cell migration. To further his studies he generated a knock-out mouse model completely lacking LR11. One of the first observations his group made was that these mice remained leaner than control animals.

I and Meizi Jiang (a postdoc in the Bujo lab) conducted a collaborative study of the LR11 knockout mice (Lr11-/-), to investigate the mechanisms by which a lack of LR11 resulted in mice being protected from diet-induced obesity.

Medical Research: What are the main findings?

Dr. Whittle: We discovered that Lr11-/- mice were indeed resistant to obesity, particularly on high fat diet and that this was not due to a reduction in food intake but rather increased energy expenditure. Further investigation showed that the white adipose tissue of Lr11-/- mice had increased expression of genes associated with thermogenesis in brown adipose tissue. Also, white adipocytes from these mice had increased thermogenic capacity. We were able to show that independently of the environmental temperature, this increase in energy expenditure in the mice was due to an increased thermogenic response to the increased caloric intake associated with high-fat diet consumption.

Our research went on to show that soluble LR11 (sLR11) was itself able to suppress thermogenesis and thermogenic gene expression in brown adipocytes. sLR11 acts as a signaling molecule which binds to bone morphogenetic protein receptors (BMPRs) on adipocytes. This binding appears to compete with and/or inhibit the action of thermogenic factors such as BMP7. These factors usually act on adipose tissue under certain conditions to induce the expression of thermogenic genes and drive white fat towards a more brown fat-like or “beige” phenotype.

Finally, we measured circulating levels of sLR11 and collected clinical data from patients with a range of bodyweights. These measurements demonstrated that more that any other biometric or disease marker, total fat mass was the best predictor of circulating sLR11 levels. In addition, in patients who underwent bariatric surgery for weight loss, the reduction in their fat mass was directly proportional to the reduction in their sLR11 levels. This further supported the notion that adipose tissue was the prominent source of sLR11

Medical Research: What should clinicians and patients take away from your report?

Dr. Whittle: I think there are two main take away messages.

The first is that there are clearly multiple layers of control and complexity within the body’s mechanisms to regulate energy storage. When formulating new anti-obesity strategies, for obvious reason, much of the focus has been on identifying the mechanisms that can increase metabolism or perhaps increase thermogenesis. However, in biological systems it is often the case that the negative regulatory arm is more fundamental as a control mechanism. Our recent study highlights that in mice, removal of the inhibitory sLR11 signal has a more potent positive effect on metabolism and energy expenditure than increasing the levels of many pro-thermogenic factors does. Imagine driving a car. There would be a far more noticeable change in the experience if you were to remove the brakes, compared to adding a slightly bigger engine!

The second thing to consider is the adaptive increase in sLR11 as fat mass increases in humans. From an evolutionary perspective it makes sense that after going to the effort to store up energy, the cells that store the fat should evolve a mechanism to more effectively guard against its overuse. However, in obese individuals the system has likely been pushed beyond its intended limits of storage. Here there is so much adipose tissue secreting sLR11 that it makes it hard for those positive metabolic signals to outweigh the chronic accumulation of the inhibitory signal. Perhaps we need to be mindful that strategies to increase thermogenesis in very obese patients will be less effective and that inhibition of sLR11 signaling might be a useful mechanism to increase the effectiveness of new and existing weight loss strategies.

A final point made by Professor Vidal-Puig is that enhancing sLR11 signaling could be extremely useful in conditions where weight loss is damaging or weight gain is incredibly difficult, for instance in patients with cachexia or anorexia nervosa.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Whittle: The pressing question now is whether we can identify conditions this increase or reduce the cleavage of LR11 to regulate the amount of sLR11 that is released into the bloodstream. While the mice we studied lacked LR11 completely, in humans a total suppression of expression is unlikely to be possible, as the full-length protein plays a neurological role; individuals with mutations in LR11 are more susceptible to Alzheimer’s disease. It may be possible that by understanding the dynamics of LR11 processing we can design dietary or therapeutic strategies to suppress sLR11 release specifically. For example, are there specific lipids and lipoproteins that rely on LR11 for import into adipocytes? Do these lipoproteins trigger more sLR11 release? These are questions we would love to find answers to.

Along similar lines, we know that in cells sLR11 alone has a huge impact on thermogenic capacity but we cannot quantify the relative contributions of the soluble and membrane-bound LR11 isoforms to metabolic control in the whole animal. Therefore we are aiming to generate a mouse that expresses a stable form of LR11 that cannot be cleaved, for use in future studies. This model my shed light on additional roles of sLR11 as a signaling molecule and provide the basis for a range of new scientific investigations.

Citation:

Whittle, AJ, Jiang, M, et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nature Communications; 20 November 2015

N.B. The work was published in Nature communications and was made possible with the support of the Wellcome Trust, the Medical Research Council (MRC) and the British Heart Foundation (BHF) in the UK. In Japan, the work was supported by

Japan Health and Labour Sciences Research grants for translational research, US-Japan cooperative medical science program, Grants-in-aid for Scientific Research and the strategic research foundation at private universities from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Dr. Andrew Whittle (2015). Circulating Protein Helps Fat Cells Resist Weight Loss

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