I have many issues with the paper but I'll ignore those and get down to the nitty gritty.
Hypothalamic remodelling.
There is normally an on-going turnover of neurons in the hypothalamus concerned with energy balance regulation. Feeding a high fat diet (high PUFA with sucrose, D12451) to mice makes them become obese and also shuts down remodelling of their hypothalamic energy balance neurons.
Here is figure 3c. It's complicated:
Let's look at the solid boxes first
The mice in the grey box described as control were simply fed D12450B throughout the experimental period and have never been obese, haven't lost any weight and have normally functioning adipocytes.
The next three groups were made obese with D12451 and then slimmed down again, through spontaneously reduced appetite, with either a high protein diet (HPD), with D12450B (HCD, same as used for the control group throughout) or with F3666 (KD). Or they were allowed to stay fat on D12451 (solid purple box).
From the solid green, blue and red boxes we can see that being post-obese, using any spontaneous weight loss diet, produces some reduction in hypothalamic neural turnover cf never-obese controls.
We can also see from the purple solid box that staying fat on D12451 causes the greatest reduction in neural remodelling.
Next are the hatched boxes. If you cut calories involuntarily, on any diet, you always reduce hypothalamic neuronal remodelling. Whether you have been overweight or not. The effect is slightly less pronounced if you calorie restrict on non obesogenic diets but more pronounced if you calorie restrict on an obesogenic diet (D12451), hatched purple box.
On top of that you have to note that the effect of an ad lib obesogenic diet is exactly the same (bad) as calorie restricting on that same obesogenic diet.
If you are simply looking for a drug-able target you would want a linear association between weight and decreased neural remodelling in the energy centre of the hypothalamus. Drug the brain stem, eat crap, lose weight, sweet.
You don't get the straight line. It's a curve, like this:
I don't think the authors have any insight in to what is going on here.
Some of us have an adipocentric view of obesity.
D12451 causes obesity because it generates pathological insulin sensitivity in adipocytes and simultaneously raises insulin. Adipocytes take in excess lipid which results in obesity combined with hunger. The calories which have been eaten are "gone" in to adipocytes. You have to eat more. To loosely quote Gary Taubes "getting fat makes you eat more".
Your hypothalamus notices, it's well aware of this caloric loss.
Eating a non obesogenic control diet does not affect hypothalmic remodelling. Eating that exact same diet at 70% of necessary calories makes you hungry and does reduce remodelling.
Eating D12451 at any calorie intake leaves you with inadequate calories. You're hungry. Remodelling shuts down. Just like you are being starved, but more so.
The relationship between bodyweight and hypothalamic remodelling is a curve because hunger is a curve. Low bodyweight hunger through frank calorie restriction "feels" the same (at least to your hypothalamus) as having a high bodyweight due to excess caloric loss in to adipocytes.
Gaining weight is a CNS hypocaloric phenomenon due to failure of adipocytes to limit caloric ingress.
Think ROS.
Please don't try to drug your hypothalamus out of obesity. It will end in tears.
Peter
EDIT: TLDR decreased hypothalamic remodelling under hypocaloric conditions "locks" signalling in the "seek calories" mode. END EDIT.
