I've been wanting to post about Wallace and Gromit, Batman and ob/ob SCD1 k/o mice for weeks now and it keeps not happening. Before we go there, just a word or two about leptin and weight gain. You can't work through anything relating to ob/ob mice (+/- SCD1 k/o) without having to, finally, sit down and read something about leptin. Or at least ob/ob mice...
To me the core question to ask is whether ob/ob mice are gaining weight because they have a brain disorder giving overeating or an adipocyte disorder storing calories. As always, there is an infinite supply of data suggesting a brain disorder, there's no denying leptin does things in the brain. The question is: Are ob/ob mice in caloric excess as they gain weight? ie Do they eat too much so gain weight or do they primarily lose calories in to their adipocytes and so have to eat more to just meet metabolic needs?
We have various rodent models of obesity which have the common feature of reducing the sympathetic nervous system drive to adipocytes, so failing to oppose insulin's lipogenic action. These animals gain fat even if you calorie restrict them. I'm thinking about hypothalamic ice-picks, various VMH neurotoxins or unprotected free radical generation. But the common thread is the loss of sympathetic nervous system driven lipolysis, facilitating insulin driven fat storage.
When confronted with the overwhelming literature on leptin it's hard to know where to start, especially when people are not asking the sorts of question which interest me, looking at the data from my very particular perspective.
I accept that ob/ob mice get fat. So too do brain injured rats and mice. Is there a common mechanism here? The smoking gun would be a period of enhanced insulin sensitivity in adipocytes, due to decreased sympathetic tone, which allows both fat gain and the preservation of insulin sensitivity in the early weeks, until adipocyte distension induced insulin resistance kicks in for the swelling adipocytes and systemic insulin resistance develops.
Of course the easy part, with absolute leptin deficiency, is asking whether leptin increases hypothalamic sympathetic nervous system outflow. That took about 30 seconds on pubmed and this was the 6th or 7th hit.
Leptin increases sympathetic drive. I think it's reasonable to conclude leptin deficiency does the converse and reduces sympathetic drive from the hypothalamus. So I'll take that as a yes. Don't forget I'm biased.
Sooooooo. Does leptin deficiency defend insulin sensitivity during rapid weight gain? As it should if the mechanism is enhanced lipid storage. And weight gain in young ob/ob mice is, well, rapid. To say the least. There will only be a very narrow window to pick up preserved insulin sensitivity before adipocyte insulin resistance and hyperinsulinaemia set in. By which time researchers have a usable model of established obesity.
I'm interested in what goes on before the model becomes "usable". We know that by rewarding volunteers to overeat we can spike their insulin levels massively within three days, probably faster. Does this happen with ob/ob mice as they over eat?
I've been working through a whole stack of papers on ob/ob mice, FFA levels, insulin levels, ketogenic diets... All the usual stuff. I ended up in a review by Lindström, giving this little gem of a quote:
"The muscle insulin resistance is not observed in very young [ob/ob] mice, but develops after 3–4 weeks "
The abstract of ref 131 supports the concept of preserved insulin sensitivity, looking at muscle rather than adipocyte insulin resistance. The papers on palmitoleate as a lipokine suggest that muscle insulin resistance is controlled by adipocyte insulin resistance, via SCD1 and palmitoleate. The paper is rather nice because it is looking at ob/ob mice as ob/ob mice, not as some completely inappropriate model for hyperleptinaemic obese humans. It was, after all, 1980 when it was published.
So to summarise:
Danish volunteers who are paid to overeat spike insulin from 35pmol/l to 74pmol/l in just three days. Mice with zero leptin overeat massively, but do not show the same insulin spike. The insulin spike signifies insulin resistance, that characteristic antioxidant defence response to an excess of calories in the metabolic milieu. This does not happen with the early overeating phase of ob/ob mice. They are in metabolic caloric deficit, which they make up by eating enough to remain vaguely functional.
Absolute leptin deficiency appears to be a very harsh driver of fat storage. Losing this many calories makes you hungry. I guess some bit of the brain is involved in converting this state of actual calorie deficit in to a feeling of hunger, but that's not what interests me nearly as much as what is happening at the adipocyte level of calorie storage.
Now we can get on to Wallace and Gromit and knocking out SCD1 in ob/ob mice.