Fat Tissue Regulation ~ Part VIII: C5L2KO v. Kit FIRKO

It's been a while since we last had a Star Wars installment.  With the War on Insulin raging out there, it seemed a good time to re-address the FIRKO mouse in this series.  You gotta admire the tireless efforts of   TWICHOOB's in rescuing a hypothesis.  It's a brave face to herald an Insurgency while one's hypothesis is circling the drain.   

There are a number of IRKO mice -- Insulin Receptor Knock Out.  There's FIRKO (Fat), LIRKO (Liver), MIRKO (Muscle), NIRKO (Brain).  Interestingly enough, two of these (M&F) are consistent with and seem to support TWICHOO, while the other two (L&N) present serious stumbling blocks (in the case of LIRKO, pretty much fatal for the hypothesis).  Allow me to introduce our characters for today's saga, C5L2KO and Kit FIRKO.  

C5L2KO is a mouse lacking the C5L2 ASP receptors on its fat cells.  FIRKO is lacking fat cell insulin receptors.  ASP, acylation stimulating protein, plays a key role in fat tissue regulation, but increasing roles in non-adipose tissues are being identified.  We've previously discussed an ASP-deficient knockout mouse:  C3KO (see Fat Tissue Regulation ~ Part II: Meet C3KO,   Fat Tissue Regulation ~ Part III: C3KO Meets Obi No Leptinobi).   The C3KO mouse is the equivalent of a Type 1 diabetic to insulin -- it lacks ASP.  These mice are resistant to obesity, and when genetically obese mice, the ob/ob's, are also made ASP deficient?  Well, these mice ate more than regular ob/ob's but didn't become as obese because of an increased metabolic rate.  So the next target was to identify a receptor for ASP and see what happens when you knock that out.  I discussed the resulting C5L2KO mouse in great detail in Part V of this series.

A summary, then, of the similarities between C5L2KO and Kit FIRKO.  Both of these ARTIFICIALLY ALTERED MICE:  

• Eat more than wild type mice
• Are resistant towards fat accumulation/obesity
• Have higher energy expenditure and fat oxidation rates
• Exhibit a unique adipose morphology where fat cells develop a two polarized versions -- small and large

OK ... so what does this mean to you and me?  Anything actionable here?  Answering the second question first, probably not unless and until some pharmaceutical agent or otherwise is identified that specifically nullifies only the fat cell insulin receptor or the ASP receptor.  Interestingly enough there may be something in the ASP pathway that can be addressed with antibodies.  ASP seems far more specific to fat tissue metabolism and regulation, whereas insulin is so ubiquitous in seemingly every tissue.  Therefore, IF we look to interfere with specific action (e.g. in fat cells) ASP may be the better target with fewer unintended side effects.

But for the foreseeable future, answering the first question, this information is more important to you and me in putting claims we hear in perspective.  If carbs drives insulin drives fat accumulation, then fat drives ASP drives fat accumulation.  Only the latter is actually through a hormone secreted by the fat tissue itself so, IMO, a far better candidate for a regulator of fat tissue mass.  It sure seems to play a role, whether that is a governing one or not remains to be seen.

I haven't blogged on this much yet, but I've got this itch to address eating disorders and such because of the vacuum surrounding how carbohydrate demonization can (and has) led to folks developing pretty serious eating disorders, including both bulimia and anorexia.  It's time someone starts talking about this a bit more.  It might as well be me ;-)