Fat Tissue Regulation ~ Part II: Meet C3KO

I've shortened the title of this series from The Full Physiological Regulation of Fat Tissue to allow for some descriptions of each installment without generating 30 word blog post titles.  Yes, I did consider TFPRFT {cheeky grin} but thought the wiser of that one! 

Allow me to introduce you to C3KO 

(note my high tech graphics skills!  LOL)

No, C3KO is not a character in Star Wars Episode MMXI*:  Battle for the Adiposity Galaxy.  Rather, there is a protein known as Complement 3, C3 for short.  The complement system is an important one in the functioning of our immune systems and has long been recognized for mediating inflammation.  In studying the role of this protein in physiology, researchers created a C3 knockout mouse -- one that does not produce C3.  This mouse is sometimes called C3KO**   

*2011 in Roman numerals

**there is apparently another C3KO mouse where "C" stands for Calpain, that is used to study muscular disorders

What does C3 have to do with fat tissue?  Well, it turns out that C3 is the precursor for the formation of acylation stimulating protein, ASP.  Indeed, another name for ASP is C3adesArg.  Without C3, the organism, in this case a mouse, is ASP-deficient.  Thus C3KO is to ASP what Type 1 Diabetes is to Insulin.  Yep ... that's where I'm going here.  If one looked for a single researcher to cite as the foremost in researching ASP, it would have to be Dr. Katherine Cianflone of McGill (here's a 1998 bio, here's the McGill search on Cianflone).  It appears that in the late 1990's Keith Frayn's group at Oxford collaborated with Sniderman and Cianflone's groups at McGill researching ASP.  This collaboration seems to have ended, with Cianflone going on to become the hands-down most prolific researcher on ASP in the ensuing years.  Meanwhile Frayn's group at Oxford seems to be researching along similar lines (postprandial lipid handling and adipokines), but for some reason has dropped ASP from his lexicon.  

I've read so much from Cianflone's group (including from her students Magdelena Maslowska and Sabina Paglialunga) this past week my head is still spinning ... and will be for some time.   There can be no doubt that ASP is a major player in adipose tissue metabolism and, it appears, in the actual regulation of fat mass.

In GCBC and WWGF, Taubes makes the argument for TWICHOO by citing cases of insulin deficiency and insulin supplementation (e.g. injected insulin therapy) and their impact on fat mass.  Basically, Type 1's who lack insulin tend to have difficulty accumulating fat, and, indeed, sudden weight loss is one reason to suspect T1 has developed.  Conversely, T1's (and T2's) tend to gain weight once insulin therapy is initiated (and, there's that picture of that poor lady's cantaloupe-sized thigh bulges from injecting insulin repeatedly in those two sites).  Therefore, insulin is *the* fattening hormone.  

Our little friend C3KO offers up the ASP-analog to T1 diabetes that I'll limit this post to.  

Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice   

Sabina Paglialunga,1,2 Alexandre Fisette,2 Yafeng Yan,2 Yves Deshaies,2 Jean-Francois Brouillette,1 Marcela Pekna,3 and Katherine Cianflone1,2

Acylation-stimulating protein (C3adesArg/ASP) is an adipokine that acts on its receptor C5L2 to stimulate triglyceride (TG) synthesis in adipose tissue. The present study investigated ASP levels in mouse models of obesity and leanness and the effect of ASP deficiency in C3 knockout (C3KO) mice on adipose tissue morphology. Plasma ASP levels in wild-type (WT) mice correlated positively with plasma nonesterified fatty acids (NEFA) (R = 0.664, P < 0.001) and total cholesterol (R = 0.515, P < 0.001). Plasma ASP was increased by 85% in obese ob/ob leptin-deficient mice and decreased in lean diacylglycerol acyltransferase 1 (DGAT1) KO mice (–54%) and C/EBPαβ/β transgenic mice (–70%) compared with WT. Mice lacking alternative complement factor B or adipsin (FBKO or ADKO), required for ASP production, were also ASP deficient. Both FBKO and C3KO mice had delayed postprandial TG and NEFA clearance on low-fat (LF) and high-fat (HF) diets, suggesting that lack of ASP, not C3, drives the metabolic phenotype. Adipocyte size distribution in C3KO mice was polarized (increased number of both small and large cells), with decreased adipsin expression (–33% gonadal HF), DGAT1 expression (–31% to –50%) and DGAT activity (–41%).

Overall, a reduction/deficiency in ASP is associated with an antiadipogenic state and ASP may provide a target for controlling fat storage.

So, they looked at three different genetic knockouts for precursors to ASP -- C3KO, FB(Factor B)KO, and AD(Adipsin)KO.  All three produced the same result of lower fat tissue accumulation and a characteristic cell size distribution (both small and large cells).  All three also resulted in a delayed postprandial clearance of triglycerides and NEFA.  These two observations make it clear that:

• ASP is involved in the uptake and esterification of dietary fats into adipose tissue, and
• ASP is involved in the regulation of fat tissue metabolism

Also of interest,

A polarization in fat cell size has been previously reported in fat-specific insulin receptor KO (FIRKO) mice.

This polarization being the mix of small and large adipocytes in the fat tissue.   ASP deficiency produces this same pattern that is seen with insulin and the FIRKO mouse.

I'm going to leave it at that for today.  Much more to come!

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For Part III, click here.