Scientists at the University of Cambridge Metabolic Research Laboratories at Addenbrooke’s Hospital, working in collaboration with colleagues at Toho University in Japan have discovered how a secreted protein acts to suppress metabolism by inhibiting a process known as thermogenesis. Most of the fat cells in the body act to store excess energy and release it when needed but some types of fat cells, known as brown adipocytes, function primarily to burn fats to generate heat to maintain body temperature. Thermogenesis has been a topic of intense interest in recent years since humans have been found to possess functional brown adipose tissue. These new findings detailing how soluble LR11 protein acts to suppress thermogenesis have been published this week in Nature Communications and may have implications for the treatment of obesity and other metabolic diseases.
The laboratories of Professor Antonio Vidal-Puig and Professor Hideaki Bujo, worked together to investigate why mice that lacked any LR11 were far more resistant to weight gain. Dr Andrew Whittle and Dr Meizi Jiang, lead authors of the paper, set about conducting experiments to carefully measure how the mice responded to different diets and specifically looked at their thermogenic responses. All mice, and in fact humans, increase their metabolic rate slightly when switched from a lower calorie diet to a higher calorie diet but the mice lacking LR11 responded with a much greater increase. Further examinations revealed how the white adipose tissue of these mice had increased expression of the genes normally associated with the more thermogenic brown adipose tissue. In line with this observation, the mice themselves were indeed more thermogenic and had increased energy expenditure, particularly following high fat diet feeding.
Lipoprotein receptors like LR11 are expressed in a number of tissues and function to facilitate the uptake of lipids for energy and cell maintenance. LR11 is interesting because it is also cleaved to produce a smaller, soluble secreted protein (soluble LR11 or sLR11), which is biologically active. The researchers were able to show that sLR11 binds to specific receptors on fat cells to inhibit their ability to activate thermogenic pathways. In effect, sLR11 acts as a signal to increase the efficiency of fat to store energy and prevents excessive energy loss through unrestricted thermogenesis. Finally they examined levels of sLR11 in humans, and found that circulating levels correlated with total fat mass. In addition, when obese patients underwent bariatric surgery, their degree of postoperative weight loss was directly proportional to the reduction in their sLR11 levels, suggesting that sLR11 is produced by fat cells, relative to their size and number. In their paper the authors hypothesize that sLR11 helps adipocytes to resist burning too much fat during transient “spikes” in other metabolic signals following short term changes to diet or environmental temperature. This in turn makes adipose tissue more effective at storing energy over long periods of time.
There is growing interest in targeting thermogenesis therapeutically, to treat obesity, diabetes and other associated conditions such as heart disease. This is because it is an attractive endogenous mechanism for disposing of excess fat in a relatively safe manner. A number of molecules have already been identified that can increase thermogenesis and/or the number of thermogenically capable fat cells. However to date there have been very few negative regulators described. These recent findings shed light on one of the mechanisms that the body employs to hold onto stored energy, where sLR11 levels increase in line with the amount of stored fat and act to prevent it being “wasted” for thermogenesis. Commenting on the relevance of the findings for human health Dr Whittle said, “If thermogenesis is to be targeted then we may also need to consider inhibiting sLR11 signaling to increase its effectiveness. Also, increased sLR11 levels may explain why overweight individuals find it incredibly hard to lose weight. Their stored fat is actively fighting against their efforts to burn it off at the molecular level.” Prof Vidal-Puig also commented “that the therapeutic potential of LR11 may also span conditions where saving energy is important such as anorexia nervosa and or cachexia”
This discovery reveals another layer of regulation that exists to control body weight and metabolism. It also highlights the multitude of ways the body has evolved to resist weight loss and provides an important insight into how we might design better strategies for treating metabolic diseases.
Reference article: Andrew J. Whittle, Meizi Jiang, Vivian Peirce, Joana Relat, Sam Virtue, Hiroyuki Ebinuma, Isamu Fukamachi, Takashi Yamaguchi, Mao Takahashi, Takeyoshi Murano, Ichiro Tatsuno, Masahiro Takeuchi, Chiaki Nakaseko, Wenlong Jin, Zhehu Jin, Mark Campbell, Wolfgang J. Schneider, Antonio Vidal-Puig & Hideaki Bujo. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans Nature Communications, 6, 8951. doi:10.1038/ncomms9951