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The ketogenic and CR (called CD in the paper below) diets
have been compared
for their effects on leptin, CR and body weight. Why would
leptin have been
relatively unaffected by CR? It appeared to be a little
less in CRers than
the control diet fed rodents. Body fat of the ketogenic
diet rodents was
more than that of CRers, who were just a little lower in fat
mass than the
control fed rodents. ß-hydroxybutyrate was lower in the
ob/ob versus wild
type rodents, although it was lower than control rodent
ß-hydroxybutyrate
levels.

Thio LL, Erbayat-Altay E, Rensing N, Yamada KA.
Leptin Contributes to Slower Weight Gain in Juvenile Rodents
on a Ketogenic
Diet.

Pediatr Res. 2006 Aug 28; [Epub ahead of print]

PMID: 16940251

Abstract:

The ketogenic diet (KD) is an efficacious therapy for
medically refractory childhood epilepsy that also slows
weight gain. We tested the hypothesis that the KD slows
weight gain via neurohormones involved in energy
homeostasis. We found that juvenile rodents fed a KD had
slower weight gain than those fed a standard diet (SD). Rats
fed a KD had higher serum leptin levels and lower insulin
levels compared with those fed an SD. We investigated the
increase in leptin further because this change was the only
one consistent with slower weight gain. Although rats fed
the SD experienced slower weight gain when calorie
restricted, they had similar serum leptin levels to those
fed the SD ad libitum. Furthermore, leptin deficient (ob/ob)
and leptin receptor deficient (db/db) mice did not show
slower weight gain on the KD. All animals on the KD had
elevated serum beta-hydroxybutyrate (betaHB) levels. Thus,
ketosis is insufficient and a functioning leptin signaling
system appears necessary for the KD to slow weight gain. The
increase in leptin may contribute to the anticonvulsant
effects of the KD.

Excerpts:


.. ketogenic diet (KD) ... juvenile rodents fed a KD
had slower weight
gain than those fed a standard diet (SD). Rats fed a KD had
higher serum
leptin levels and lower insulin levels compared with those
fed an SD. We
investigated the increase in leptin further because this
change was the only
one consistent with slower weight gain. Although rats fed
the SD experienced
slower weight gain when calorie restricted, they had similar
serum leptin
levels to those fed the SD ad libitum. Furthermore, leptin
deficient (ob/ob)
and leptin receptor deficient (db/db) mice did not show
slower weight gain
on the KD. All animals on the KD had elevated serum
beta-hydroxybutyrate
(betaHB) levels. Thus, ketosis is insufficient and a
functioning leptin
signaling system appears necessary for the KD to slow weight
gain. The
increase in leptin may contribute to the anticonvulsant
effects of the KD.
Abbreviations: ß-HB, ß-hydroxybutyrate; CD, calorie
restricted diet;
db/db, homozygous leptin receptor deficient mice; DEXA, dual
energy x-ray
absorptiometry; KD, ketogenic diet; ob/ob, homozygous leptin
deficient mice;
PD, postnatal day; SD, standard diet

[...]

... Although another study concurs with our observation
of higher leptin
and lower insulin levels in KD-fed rats compared with SD-fed
rats (22), we
cannot explain the contrasting observations in humans with
rheumatoid
arthritis or type 2 diabetes who exhibit lower leptin levels
on a KD
(16,23). ... our results suggest that ketosis alone cannot
slow weight gain
because the KD caused ketosis in ob/ob and db/db mice
without slowing weight
gain. We do not know the reason for this discrepancy, but
ß-HB may require
leptin to alter energy balance. Overall, our results
indicate that an intact
leptin signaling system is necessary and that ketosis is
insufficient for
the KD to slow weight gain.

Our results differ from those of a recent study that
found increased
ghrelin levels in rats fed a KD (22). We might predict such
an increase
because ghrelin levels rise in association with the slower
weight gain
observed in rats on protein-restricted diets (19). Although
the low protein
content of the KD we used may have contributed to our
findings (7), the lack
of a change in ghrelin and three other observations suggest
that it is not
the only factor involved. First, the KD maintained normal
weight gain in
ob/ob and db/db mice. Second, rats fed the KD showed relatively
well-preserved lean mass when expressed as a percentage of
body mass. Third,
peak leptin levels on the CD did not exceed trough leptin
levels on the SD
despite the slower weight gain on the CD.

Ultimately, the KD must increase energy expenditure
over energy intake
to slow weight gain. The KD had variable effects on
normalized caloric
intake despite consistently slowing weight gain. It
decreased caloric intake
in C57BLKS/J, db/db, and ob/ob mice, had no effect on
caloric intake in
C57BL/J6 mice, and increased caloric intake in
Sprague-Dawley rats. Although
the oily consistency of the KD chow made caloric intake
measurements
difficult, overall our findings suggest that the KD can
decrease food intake
and increase energy expenditure, which are known effects of
leptin (8).


Our results support the hypothesis that the KD exerts
its anticonvulsant effects by activating a variety of
potassium channels via the
metabolic changes it induces (27). We speculate that the
KD-induced rise in
serum leptin increases brain leptin levels because brain
levels are
proportional to serum levels (28). We expect a diffuse
increase in brain
levels because leptin transporters exist throughout the
brain (28) and
leptin increases throughout the brain when administered
exogenously (29).
Leptin can act as an anticonvulsant throughout the brain
because leptin
receptors exist throughout the brain (28) and activate
calcium-activated
potassium channels (9). However, the decline in insulin may
counteract some
of the effects of the rise in leptin because insulin
activates the same
channel (10). In summary, we hypothesize that the KD
produces a net
anticonvulsant effect in part because increased brain leptin
activates
potassium channels. This mechanism may be unique among
antiepileptic drugs,
which do not increase leptin independent of weight gain
(30-32). Our results
do not exclude leptin modulation of neuronal or glial energy
homeostasis or
other mechanisms involving the complex metabolic and
cellular effects of the
KD from contributing to its anticonvulsant properties (27).
Despite our focus on leptin, other neurohormones may
contribute to the
anticonvulsant and weight effects of the KD. For example,
the increased
cortisol levels we found in rats on the KD mirrors the
increase seen in
children on the KD and may contribute to the anticonvulsant
effect of the
diet (33). Others have considered the possibility that
changes in
neuropeptide Y and galanin expression contribute to the
effects of the KD,
but the diet does not change their brain mRNA levels (34).
Rather than
excluding a contribution of other neurohormones, our results
indicate that
studying KD-induced changes in neurohormones involved in
energy homeostasis
may help elucidate the mechanisms underlying the
anticonvulsant and weight
effects of the KD.