Since the value of the research discussed in the lay article “Enzyme boosts metabolism, prevents weight gain in mice” is hidden by what seems to be the author’s lack of knowledge in this subject area, here is a summary from the paper itself:
Information surrounding obesity, inflammation, and insulin resistance is usually presented in a linear fashion—obesity causing widespread inflammation leading to insulin resistance and therefore type II diabetes. To get a better grasp on the relationships between these three, Ping Jiao et. al. (2012) engineered a mouse that was inflamed though not obese. More importantly they had over expressed a pathway in these mice specifically involved in obesity-related inflammation, achieved by expressing a constituently active form of IKKβ that is found in human adipocytes. This essentially just skipped the first part of this cause and effect relationship, looking at inflammation independent of obesity.
Four groups of mice were studied—those that expressed IKKβ were compared to those without after given either a high fat or a regular chow diet. The researchers concluded that these transgenic mice not only had a lower body weight, but also had improved tolerance to glucose and insulin despite increased inflammation. The presence of inflammation was determined by looking at the levels of mRNA coding for TNFα, IL-6, and MCP-1 where the transgenic mice had statistically increased amounts of both IL-6 and MCP-1, though no increase in TNFα. Separate tests determined possible mechanisms behind the increase in energy expenditure, where mRNA levels in brown adipose tissue and muscle were quantified. Increased expression of genes involved in thermogenesis and beta-oxidation in these tissues seem to play a key role in the increased metabolism.
These findings suggest that it is the direct consequences of obesity rather than inflammation that attribute to decreased insulin sensitivity. As Xu mentions in the lay article “Lower body weight is always a beneficial thing for influencing insulin sensitivity…Reduced adiposity wins over increased inflammation.” Possible explanations may be the decrease in free fatty acids or increased energy expenditure of the thinner, inflamed mice. This was an interesting twist after a semester discussing the detriments of unregulated inflammation. Thoughts?
Sources:
Enzyme boosts metabolism, prevents weight gain in mice.
http://medicalxpress.com/news/2011-11-enzyme-boosts-metabolism-weight-gain.html
Constitutive Activation of IKKβ in Adipose Tissue Prevents Diet-Induced Obesity in Mice.
Jiao, Ping, Feng B, Ma J, Nie Y, Paul E, Li Y, Xu H.
Endocrinology. January 2012; 153(1)
Note: I was unable to find the research article for free the second time I tried, but have it on my computer if anyone has trouble finding it.
Fascinating article, I hadn't seen it, and it cerrtainly pertains to my work. Inflammation in a very global sense has been implicated as a player in a vast majority of what we clinicians who work in obesity would regard as obesity related co-morditities. These include obesity itself, non-alcoholic fatty liver disease, type 2 diabetes mellitus, obstrutive sleep apnea, cardiac events, icnluding stroke and myocardial infarctions. In my personal research program on the mechanisitic links of obstructive sleep apnea and non alcoholic fatty liver disease, here at Chidlren's Colorado, we are looking carefully at the balance of pro and anti-inflamamtory cytokines using cytokine profile analysis via an MSD platform technique.
ReplyDeleteThis comment has been removed by the author.
ReplyDeleteElevated levels of plasma fatty acids and high dietary fat intake are conditions implicated in many of the diseases both of you have mentioned. However, recent data suggest that because of these conditions, high levels of fat accumulate in the liver and muscle, known as intramyocellular lipids (IMCL), and is associated with the development of insulin resistance. In the (pre)diabetic state, reduced expression of the transcription factor PPARgamma co-activator-1alpha (PGC-1alpha), which is involved in mitochondrial biogenesis, has been suggested to underlie the reduced mitochondrial function. Importantly, the reduction in PGC-1alpha may be a result of low physical activity, consumption of high-fat diets and high plasma fatty acid levels. Mitochondrial function can also be impaired as a result of enhanced mitochondrial damage by reactive oxygen species that can induce oxidative damage on DNA, RNA, and proteins and can potentially lead to inflammation.
ReplyDeleteSchrauwen, P. High-fat diet, muscular lipotoxicity and insulin resistance. Proc Nutr Soc. 2007, 66(1):33-41.
This comment has been removed by the author.
ReplyDeleteAnother interesting perspective is from the adipokine adiponectin. This is an anti-inflammatory cytokine secreted by adipocytes. Yamauchi et al., 2001, showed that decreased expression of adiponectin correlates with decreased insulin resistance in mouse models. Adiponectin decreases insulin resistance by decreasing triglyceride content via the increased activity of fatty acid metabolism in muscle.
ReplyDeleteIt has also been recently enumerated that angiogenesis modulates adipogenesis and obesity. Adipose tissue has been long known to promote wound healing and to revascularize ischemic tissues. Brakenhielm et al. 2004 found that the angiogenesis inhibitor TNP-470 increases insulin sensitivity in obese animals. These results together suggest that antiangiogenic agents may help sensitize insulin resistance.
Brakenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P, Cao Y. Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res. 2004 25;94(12):1579-88.
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001, 7(8):941-6.
Interesting article for me as well. I am working on a study for subjects with the metabolic syndrome. If we look at people who have the metabolic syndrome (a collection of risk factors including visceral obesity, increased trig's, decreased HDL's, high blood pressure, and glucose over 100) we see a huge increase in risk for diabetes and cardiovascular disease. Metabolic syndrome also correlates with increased levels of CRP, decreased levels of adiponectin, and increased insulin resistance. Julez's comment is especially interesting because it seems to be saying that decreased adiponectin can actually lead to increased insulin sensitivity, the opposite of what one would infer based off of metabolic syndrome findings. It also looks like increase in CRP, an inflammatory marker, may not tell us why these people have an increased risk of disease, but only indicate that they are obese (which we already know because of the visceral obesity component). It looks like a lot more research needs to be done. Is inflammation being used to combat the bad effects of obesity? Is it a neutral byproduct of obesity? It's role seems very ambiguous, and hopefully more research on mouse models along with human studies on things like metabolic syndrome can help us understand it more.
ReplyDelete