BMP7 Activates Brown Adipose Tissue and Reduces Diet-Induced Obesity Only at Subthermoneutrality

Abstract

Background/AimsBrown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity.Methods and ResultsHigh-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21°C or 28°C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21°C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28°C. Additionally, BMP7 resulted in extensive ‘browning’ of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia.ConclusionTogether, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders.

Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

“…Importantly, this effect was only observed when BMP7 was injected in combination with the β3-adrenergic receptor agonist, CL316,243, [154]. This was further corroborated by an interesting study showing that BMP7's positive effects on thermogenesis, BAT activity, lipolysis, and browning of WAT were only evident at sub-thermoneutrality [190]. Thermoneutrality is defined as the temperature at which homeotherms are no longer required to expend energy to maintain their body temperature.…”

Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

“…A key finding was that mice simultaneously challenged with vHFD and treated with IL-37 did not gain weight as compared to vehicle-injected mice on the same vHFD. This finding may be due to energy expenditure in adipose tissue and muscle (25,45), adipose tissue browning or appetite change which are known to regulate body weight and high-fat diet induced obesity in mice (59)(60)(61). In addition, as discussed above, it would be intriguing to further study the effect of IL-37 on glucose stimulated insulin secretion in this vHFD model as well.…”

Wheat gluten intake increases weight gain and adiposity associated with reduced thermogenesis and energy expenditure in an animal model of obesity

“…In SAT, gluten also reduced BMP7 expression in CD-G and HFD-G animals. This protein induces extensive 'browning' of white adipose tissue, regardless of the environmental temperature (19). BMP7 is important for brown adipocyte differentiation and UCP1 expression and it increases in energy expenditure (20).…”