pyruvate and hydroxycitrate:carnitine may synergize to promote reverse electron transport in...

ROLE OF REVERSE ELECTRON TRANSPORT INKETOGENESIS

Recent anecdotial clinical experience strongly suggests

that pyruvate administration (4 g orally t.i.d.) interacts

synergistically with hydroxycitrate (HCA) and carnitine

to promote rapid fat loss and marked thermogenesis (see

Appendix).

HCA/carnitine has been recommended as a diet aid on

the basis of its presumed ability to promote the transport

of free fatty acids (FFAs) into hepatic mitochondria (1–3).

This transport step is believed to be rate-limiting for

hepatic ketogenesis (4,5). More specifically, the conver-

sion of cytoplasmic fatty acyl coA to fatty acyl carnitine

via the enzyme carnitine palmitoyl transferase I (CPT) is

pace-setting for fatty acid transport into mitochondria

and thus for ketogenesis (4,5). HCA – the chief acid found

in fruits of the genus Garcinia – disinhibits CPT by sup-

pressing synthesis of malonyl coA, a key allosteric inhi-

bitor of this enzyme (6); it achieves this by acting as a

potent competitive inhibitor of citrate lyase (7–9), whose

activity in hepatocytes is required for the cytoplasmic

generation of acetyl coA, the biosynthetic precursor of

malonyl coA. Carnitine is the essential cofactor for CPT

activity, and ordinary non-fasting hepatocyte levels of

this coenzyme appear to be subsaturating, such that

provision of extra carnitine accelerates hepatocyte keto-

genesis when CPT is activate (4). Thus, it has been

Medical Hypotheses (1999) 52(5), 407–416© 1999 Harcourt Brace & Co. LtdArticle No. mehy.1997.0683

Pyruvate and hydroxycitrate/carnitinemay synergize to promote reverseelectron transport in hepatocytemitochondria, effectively ‘uncoupling’the oxidation of fatty acids

M. F. McCarty, J. C. GustinNutriGuard Research, Encinitas, CA, USA

Summary In a recent pilot study, joint administration of pyruvate, hydroxycitrate (HCA), and carnitine to obesesubjects was associated with a remarkable rate of body-fat loss and thermogenesis, strongly suggestive of uncoupledfatty-acid oxidation. Hepatocytes possess an uncoupling mechanism – reverse electron transport – that enablesfasting ketogenesis to proceed independent of respiratory control. Electrons entering the respiratory chain at thecoenzyme Q (CoQ) level via FAD-dependent acyl coA dehydrogenase, can be driven ‘up’ the chain by theelectrochemical proton gradient to reduce NAD+; if these electrons are then shuttled to the cytoplasm, returning to therespiratory chain at the CoQ level, the net result is heat generation at the expense of the proton gradient, enabling theuncoupled flow of electrons to oxygen. Pyruvate’s bariatric utility may stem from its ability to catalyze the rapidtransport of high-energy electrons from mitochondria to the cytoplasm, thus stimulating electron shuttle mechanisms.By enabling rapid mitochondrial uptake of fatty acids and thus disinhibiting hepatocyte ketogenesis, HCA/carnitineshould initiate reverse electron transport: concurrent amplification of electron shuttle mechanisms by pyruvate can beexpected to accelerate this reverse electron transport, thereby decreasing the electrochemical proton gradient. As aresult, hepatocytes may be able to convert fatty acids to CO2 and heat with little net generation of ATP. Theseconsiderations suggest that it may be feasible to render hepatocytes functionally equivalent to activated brown fat,such that stored fat can be selectively oxidized in the absence of caloric restriction. Other measures which enhancethe efficiency of hepatocyte electron shuttle mechanisms may increase the efficacy of this strategy.

Received 2 September 1997Accepted 15 October 1997

Correspondence to: Mark F. McCarty MD, NutriGuard Research, 1051Hermes Avenue, Encinitas, CA 92024, USA

407

proposed that joint administration of HCA and carnitine

will be clinically useful as a strategy for disinhibiting and

activating CPT, thereby stimulating ketogenesis.

Although the process of ketogenesis reduces both

NAD+ and FAD, the rate of ketogenesis appears to be

substantially independent of respiratory control (10–13),

i.e. it can proceed at a high rate even when hepatocyte

metabolism is generating ADP at a low rate. The most

reasonable explanation for this phenomenon has been

offered by Berry and co-workers (11,13). They suggest

that, during ketogenesis, high-energy electrons enter

the respiratory chain at a greater rate than hepatocytes

can generate ADP, resulting in an electron glut and an

increased electrochemical proton gradient. Under these

circumstances, electrons entering the chain at the level of

coenzyme Q (via the FAD-dependent acyl coA dehydro-

genase reaction) can be ‘pushed’ up the respiratory chain

to NAD dehydrogenase, which transfers them to NAD+.

These electrons can then be shipped to the cytosol via

the malate/aspartate shuttle and, after reducing NAD+

or NAD(P) in the cytosol, can then re-enter the mito-

chondrial respiratory chain at the coenzyme (CoQ) level

via the glycerol-3-phosphate shuttle. The ‘reverse elec-

tron transport’ step in this cycle is driven by the electro-

chemical proton gradient of the mitochondrial inner

membrane – which diminishes as a result – or, alterna-

tively, by conversion of ATP to ADP via the mitochondrial

ATP synthase. After two ‘turns’ of this cycle, the electro-

chemical proton gradient will be sufficiently diminished

to enable the electrons to pass down the respiratory chain

from CoQ to oxygen, without any obligate coupling to

ATP synthesis. (Alternatively, the two ADPs generated by

two turns of the cycle will enable the coupled transport

of these electrons from CoQ to oxygen.) This mechanism

thus would effectively ‘uncouple’ the transfer of electrons

from FADH2 to oxygen during ketogenesis. This ‘reverse

electron transport’ mechanism is well documented in

mitochondria and sub-mitochondrial particles in vitro

(14–18); its role in vivo is still speculative, but it seems

to offer a very plausible explanation for the mysterious

uncoupling of hepatic ketogenesis.

PYRUVATE PROMOTES ELECTRON SHUTTLEMECHANISMS

The well-documented bariatric benefits of pyruvate

(19–24) remain unexplained. We propose that adminis-

tration of pyruvate enhances the efficiency of the shuttle

mechanisms required for reverse electron transport, by

serving as a biosynthetic precursor for key substrates

of these shuttles – namely oxaloacetate and dihydroxy-

acetone phosphate; it is also conceivable that pyruvate

has an as-yet-uncharacterized allosteric effect on the acti-

vity or synthesis of enzymes which catalyze the shuttles.

When concurrent administration of HCA/carnitine disin-

hibits hepatic ketogenesis, flooding hepatic mitochondria

with reducing equivalents and initiating reverse electron

transport, the pyruvate-mediated activation of shuttle

mechanisms may substantially amplify the rate of reverse

electron transport, such that not only ketogenesis, but

also Krebs cycle activity is at least partially uncoupled,

enabling the complete oxidation of FFAs to CO2 with

little net production of ATP and a substantial release of

heat. Thus, we propose that, under these circumstances,

electrons transferred to NAD+ from the Krebs cycle can

be ‘shuttled’ to enter the respiratory chain at the CoQ

level, and that a portion of these electrons will then

be subjected to reverse electron transport – thereby

diminishing the electrochemical proton gradient and

enabling uncoupled respiration.

The efficient conversion of pyruvate to mitochondrial

oxaloacetate may be crucial to pyruvate’s utility. The

rapid production of acetyl coA during ketogenesis can

be expected to strongly activate pyruvate carboxylase,

whereas pyruvate dehydrogenase will be inhibited (l,2).

Furthermore, the generation of ketone bodies from excess

acetyl coA will promote pyruvate transport into mito-

chondria. Thus, pyruvate administered during ketogenesis

should be rapidly converted to mitochondrial oxalo-

acetate. Owing to the high redox potential in ketogenic

mitochondria, and the fact that reduction of oxaloacetate

is highly exergonic, much of this oxaloacetate will be

quickly reduced to malate, which readily exits mito-

chondria. In this way, pyruvate can be expected to catalyze

the transfer of high energy electrons from mitochondria

to the cytosol. The resulting decrease in mitochondrial

NADH should stimulate the Krebs cycle and promote

reverse electron transport. Provided that efficient en-

zymatic machinery is in place to transfer electrons from

cytoplasmic malate to dihydroxyacetone phosphate,

and to oxidize the resulting glycerol-3-phosphate at the

mitochondrial inner membrane, the ‘exported’ electrons

can be quickly returned to CoQ in the respiratory chain,

enabling further reverse electron transport.

Indeed, if one were to logically devise an optimal method

for expediting the transport of excess high-energy elec-

trons from mitochondria, one could probably do no better

than to administer an agent which, like pyruvate, promotes

the rapid intramitochondrial generation of oxaloacetate.

(A ‘Trojan horse’ such as pyruvate is required to increase

mitochondrial oxaloacetate levels, since oxaloacetate

itself cannot cross the mitochondrial inner membrane.)

This may hold the key to pyruvate’s bariatric utility –

even in the absence of reverse electron transport, pyruvate

should catalyze the shuttle-mediated ‘discounting’ of

high-energy electrons, whereby electrons flow from

mitochondrial NADH through the cytoplasm to enter the

respiratory chain at CoQ.

408 McCarty and Gustin

Medical Hypotheses (1999) 52(5), 407–416 © 1999 Harcourt Brace & Co. Ltd

Figure 1 demonstrates how it would be theoretically

conceivable for reverse electron transport to completely

uncouple hepatocyte oxidative metabolism. If keto-

genesis and Krebs cycle activity transfer reducing equi-

valents to NAD+ and FAD at rates x and y, respectively,

then a net reverse electron transport from CoQ to NAD+

at a rate of 2(x+y) would collapse the electrochemical

proton gradient sufficiently (or generate sufficient ADP)

to enable respiration in the absence of net ATP produc-

tion, i.e. FFAs (and any other substrate oxidized by

hepatic mitochondria) could be converted to CO2 and

heat at a rate independent of hepatocyte metabolic

activity. In practice, respiration will be partially coupled,

as hepatocytes have metabolic needs that generate ADP –

thus, it cannot be expected that reverse electron transport

will ever achieve a rate as high as 2(x+y). Nonetheless,

a considerable degree of uncoupling can be anticipated

if reverse electron transport can be substantially boosted.

Electron flow during reverse electron transport may

well proceed in an oscillatory fashion. Reverse electron

flow will gradually collapse the electrochemical proton

gradient, slowing the reverse flow but accelerating

forward flow to oxygen. The increased forward flow,

to the degree that it is uncoupled, will ‘recharge’ the

proton gradient, slowing forward flow but promoting

an increased rate of reverse flow. (And so, to quote the

King, ‘et cetera, et cetera, et cetera’.)

Pyruvate supplementation should also have thermo-

genic effects that drive the coupled oxidation of FFAs – by

stimulating the futile cycle pyruvate → oxaloacetate

phospho-enol-pyruvate → pyruvate, utilizing one net

ATP (or if malic enzyme is induced, the cycle pyruvate

→ oxaloacetate → malate → pyruvate), and by acting as

substrate for gluconeogenesis, which requires 2ATP

equivalents plus an NADH per molecule of pyruvate

converted to glucose. The activation of pyruvate carbo-

xylase by HCA/camitine should promote these mecha-

nisms. The mitochondrial oxaloacetate generated from

pyruvate will also aid Krebs cycle activity, and the

pyruvate-stimulated production of malate will accelerate

mitochondrial uptake of anionic substrates such as

pyruvate and phosphate. An increase in hepatocyte malate

levels is typically seen in response to measures – exercise

and gluconeogenic hormones – that boost the respiratory

capacity of hepatocyte mitochondria (25).

It can be anticipated that, even with the concurrent use

of pyruvate, a proportion of the acetyl coA generated

from fatty acids will not be oxidized, but rather exported

from the liver as ketone bodies, committed to oxidation

in peripheral tissues. This peripheral oxidation of ketones

will presumably be coupled, but will in any case complete

the selective oxidation of fats, such that a low respiratory

quotient favorable to fat loss is achieved. Ketosis can

also suppress adipocyte lipolysis (26); while this may slow

the rate of fat loss, it should have a favorable impact on

cardiovascular risk factors. Some of the electrons evolved

during hepatocyte fatty acid oxidation will not flow to

oxygen, but rather will be used to convert acetoacetate

to beta-hydroxybutyrate.

SHUTTLE FUNCTION AS A KEY TOTHERMOGENESIS

It undoubtedly is not coincidental that the thermogenic

hormones thyroxine and (in rats) high-dose DHEA

potently induce the expression of two enzymes in hepato-

cytes – the mitochondrial glycerol-3-phosphate dehydro-

genase and the cytoplasmic malic enzyme – which can be

rate-limiting for electron shuttle mechanisms (27,28);

cafeteria-feeding’, which is potently thermogenic, has an

analogous effect (13,30). Catecholamines – also thermo-

genic for hepatocytes – activate mitochondrial glycerol-

3-phosphate dehydro-genase by increasing hepatocyte

intracellular calcium levels (31). Even in the absence

of reverse electron transport, the transfer of electrons

from mitochondrial NADH to respiratory chain CoQ via

these shuttle mechanisms effectively lowers the P:O ratio

from 3 to 2 – thus partially uncoupling hepatic oxidative

metabolism. Clearly, however, the greatest degree of un-

coupling can be anticipated when an up-regulation of

shuttle mechanisms is allied with a disinhibition of keto-

genesis that initiates reverse electron transport. We pro-

pose that this is precisely what happens when pyruvate

is administered in conjunction with HCA/carnitine.

Alternate means of up-regulating shuttle function might

be expected to synergize with these measures. Whereas

high-dose DHEA is not suitable for clinical use (owing to

its ability to give rise to excessive levels of sex hormones),

Lardy and colleagues have recently demonstrated that

7-hydroxy or 7-keto derivatives of DHEA – which to some

degree are produced endogenously, and do not give rise

to sex-hormone activity – are actually more potent than

Pyruvate, HCA and carnitine in ‘uncoupling’ the oxidation of FFAs 409

© 1999 Harcourt Brace & Co. Ltd Medical Hypotheses (1999) 52(5), 407–416

Fig. 1 Uncoupling of hepatocyte respiration via reverse electrontransport.

DHEA itself in inducing thermogenic shuttle enzymes

(as well as fatty acyl coA oxidase) in rat hepatocytes

(32,33). If these agents prove to be effective in this regard

in humans, without unacceptable side-effects or toxicities

(such as are seen with thyroid hormone), they may well

have a bright future in bariatric medicine, alone or in

conjunction with the techniques suggested here.

Folkers has demonstrated that many individuals are

functionally deficient in CoQ, in the sense that addition

of CoQ to their mitochondria can enhance the oxidation

of succinate by succinate dehydrogenase (34). Could

CoQ levels likewise sometimes be rate-limiting for the

glycerol-3-phosphate shuttle and reverse electron trans-

port? If so, supplemental CoQ might sometimes enhance

the efficacy of the measures recommended here. Some

years ago, an open study by Van Gaal provided evidence

that correction of documented CoQ deficiency (as assessed

by succinate dehydrogenase activity) might accelerate

weight loss in dieters (35).

If pyruvate’s bariatric utility is primarily reflective of

the fact that it is an efficient precursor for mitochondrial

oxaloacetate (as noted above, the possibility that it has

direct inductive effects cannot presently be discounted),

it is possible that aspartic acid will have comparable

activity. Aspartate is avidly transported into mitochondria

and de-aminated to yield oxaloacetate, as a key portion

of the malate-aspartate shuttle; as noted, oxaloacetate

cannot directly enter mitochondria, but can do so when

‘disguised’ as aspartate. If aspartate is in fact effective in

this regard, this may be of some practical importance as

aspartates are currently far less expensive than pyruvates.

(It may be noted that the process of de-amination and the

subsequent conversion of NH4+ to urea will expend an

additional 4 ATPs – but also requires reduction of NAD+.)

Lactic acid, likewise inexpensive, is readily converted

to pyruvate and thus might be considered as an alter-

native to this compound. However, the oxidation of

lactate to pyruvate would be expected to increase cyto-

plasmic redox potential, which could slow the rate of

electron transport from mitochondria to the cytoplasm.

It should be noted that Stanko’s original testing of

pyruvate and dihydroxyacetone as remedies for ethanol-

induced fatty liver (36), was rooted in the fact that these

compounds can function as electron acceptors – whereas

lactate is clearly an electron donor. However, there are

alternative pyruvate precursors – the amino acids serine

and glycine – that do not mediate reductions when con-

verted to pyruvate. Alanine, however, may be inappro-

priate for this purpose, as it is an inhibitor of pyruvate

kinase.

With regard to the demonstrated utility of dihydroxy-

acetone as an aid to thermogenesis in animals (19), it

should be noted that phosphorylation of this compound

yields the oxidized component of the glycerol-3-

phosphate shuttle. Thus, dihydroxyacetone appears to be

a preferable (though much more expensive) alternative

to glycerol. The latter compound appears to have a tem-

porary anorexic activity in rat (37), although controlled

clinical evaluations of its impact as an adjuvant to low-

calorie diets have failed to confirm efficacy in this regard

(38,39). Hepatocyte levels of dihydroxyacetone phosphate

can be increased most conveniently with fructose; the

liver-specific fructokinase produces fructose-1-phosphate,

which is then cleaved by aldolase to yield glyceraldehyde

and dihydroxyacetone phosphate. While fructose aloneis clearly not a diet aid, it would be interesting to deter-

mine whether catalytic amounts might stimulate reverse

electron transport in the context of the measures re-

commended here. Dihydroxyacetone phosphate levels

should also be increased somewhat by gluconeogenic

prescursors –including pyruvate and aspartate.

ACTIVATION OF PYRUVATE KINASE WITHMETFORMIN AND BIOTIN

The drug metformin may also have utility as an adjuvant

in this weight-loss strategy (3). By activating flux through

pyruvate kinase (40,41), metformin may enhance endo-

genous generation of pyruvate, decrease the loss of

administered pyruvate to gluconeogenesis, and con-

currently enhance the thermogenic impact of the futile

cycles centered on pyruvate. The tendency of metformin

to promote weight loss and decreased appetite in dia-

betics is well known (42–45). Its use in conjunction with

ketogenic techniques, in diabetics or borderline diabetics,

may in any case be desirable to prevent excessive stimu-

lation of gluconeogenesis by accelerated hepatic FFA

oxidation (40,44,46–51).

An alternative (or adjunctive) approach to activating

pyruvate kinase may be offered by high-dose biotin.

In rodent studies, pharmacological doses of biotin can

produce significant increases in the expression of gluco-

kinase in both hepatocytes and pancreatic β cells (52–56);

activation of guanylate cyclase by supraphysiological

concentrations of biotin may mediate this effect (57,58).

Increased activity of glucokinase in hepatocytes can be

expected to increase pyruvate kinase activity – both by

enhancing the level of its allosteric activator, fructose-

1,6,-dipkosphate, and by stimulating increased synthesis

of the enzyme (59–62). An elevation of glucokinase should

aid electron shuttle function by increasing the concentra-

tion of dihydroxyacetone phosphate, and can be expected

to promote thermogenic ‘futile cycles’ involving glycolytic

intermediates (61). A further benefit of biotin could be

that, by increasing glucokinase activity in β cells, it may

act to offset a potential adverse effect of high-dose HCA

on glucose-stimulated insulin secretion (63). A recent

report that biotin lessens weight gain (presumably, fat



gain) in a congenitally obese strain of rat – despite slightly

increasing food intake – suggests that biotin does indeed

have thermogenic potential (64). Since 3 mg t.i.d. has

been shown to aid glycemic control in human diabetics

(65), this dose schedule is likely to be adequate for

increasing hepatocyte glucokinase activity clinically.

A THERMOGENIC ROLE FOR GLUCAGON

In the pilot study described in the Appendix, patients

were advised to perform fasting aerobic exercise and to

eat substantial amounts of protein. Each of these measures

can be expected to increase glucagon activity. Glucagon

promotes intramitochondrial fatty acid transport and

ketogenesis, both by decreasing the synthesis of malonyl-

coA (via suppression of acetyl-coA carboxylase activity)

and by decreasing the potency of malonyl-coA as an

allosteric inhibitor of carnitine palmitoyl transferase

(66,67); thus, measures which enhance glucagon activity

have been recommended as adjuvants to HCA/carnitine

(2). Glucagon’s ability to stimulate pyruvate carboxylase

and thus promote gluconeogenesis may simply reflect

allosteric activation by the increased levels of acetyl-coA

stemming from accelerated fatty acid oxidation (68);

glucagon also promotes mitochondrial uptake of pyruvate

(25,69). Mitochondria from glucagon-treated animals

have greater respiratory activity ex vivo (70); this is due

in part to increased efficiency of electron flow from

NADH through NADH dehydrogenase to CoQ (71). It

seems not unlikely that, conversely, glucagon could

increase the efficiency of reverse flow from CoQ to NADH

during ketogenesis, though experimental demonstration

of this appears to be lacking. Homeostatically, it would

make good sense for glucagon to increase the efficiency

of reverse electron transport, thereby promoting more

rapid ketogenesis. Glucagon acts as a signal of carbo-

hydrate deficiency, inducing the conversion of the body’s

chief stored substrates, protein and fat, to glucose and

ketones (respectively), thus helping to ‘fuel’ the central

nervous system during starvation. Efficient ketogenesis

is evidently crucial in this regard, as it enables sparing of

tissue protein.

When insulin levels are low, glucagon infusion has a

marked thermogenic impact in humans (72); stimulation

of gluconeogenesis and ureagenesis undoubtedly contri-

butes to this effect. As these processes are driven by ATP,

they can be expected to promote the coupled oxidation

of hepatic lipid. A high protein intake will activate these

processes, both by stimulating glucagon output, and

by providing substrate for them. In the context of the

measures recommended here, the chief benefit of these

endergonic processes may be that they stimulate electron

flow from the Krebs cycle, for which ADP is an allosteric

activator.

OVERVIEW

There may be a certain logical inevitability to the ideas

proposed here. The clinical results described in the

Appendix can only credibly be attributed to a substantial

uncoupling of fatty acid oxidation. Since HCA/carnitine

can be expected to have its most profound impact on the

liver, this is likely to be the chief site of this uncoupling.

The other major thermogenic organ in man is skeletal

muscle; since pyruvate has been shown to enhance

exercise endurance (73,74), it seems most unlikely that

pyruvate promotes uncoupling in muscle. The liver is

known to have a mechanism for uncoupled oxidative

metabolism – reverse electron transport – which should

be stimulated by HCA/carnitine. It is therefore logical to

suspect that an amplification of this mechanism is respon-

sible for the uncoupling observed during joint adminis-

tration of pyruvate and HCA/carnitine. Pyruvate’s role

as an efficient precursor for mitochondrial oxaloacetate

suggests that pyruvate administration will indeed aid

reverse electron transport.

It is very clear to us that the results reported in the

Appendix demonstrate a marked synergism between

pyruvate and HCA/carnitine. When used in conjunction

with low-calorie diets or an overfeeding regimen, pyruvate

(at 15–30 g daily) diminished body fat by about 1 kg over

21 days relative to placebo (22–24); in the context of a

low-fat weight-maintaining regimen in hyperlipidemic

subjects, about half of whom were obese, the incremental

fat loss associated with pyruvate (22–44 g daily) was

0.4 kg over six weeks (75). In a double-blind study in

which overweight volunteers received HCA/carnitine/

chromium picolinate while asked to avoid fatty foods, eat

more fiber, and get more physical activity, the additional

fat loss attributable to the supplement was 0.6 kg over

four weeks (76). Used alone, either of these techniques

appears to have some utility, but they should rightly be

construed as adjuvants to traditional weight-management

techniques. The results reported here with the combineduse of these measures are clearly far greater than the sum

of their individual efficacies and, if confirmable, suggest

a new and definitive approach to obesity control.

If indeed it is possible to at least partially uncouple FFA

oxidation in the liver, this organ might reasonably be

compared to a vast slab of activated brown fat. Under

these circumstances, unprecedented rates of selective fat

loss can be anticipated.

The liver evidently can only degrade FFAs that reach

it. Thus, these methods should have their most rapid

impact on fat stores – such as visceral adipocytes – that

are relatively lipolytically active. Indeed, diets and exer-

cise regimens that successfully achieve fat loss tend

to have a disproportionate impact on visceral fat stores

(77–80). A reduction in lipolytically active fat stores can



be expected to be of practical benefit with respect to the

insulin resistance syndrome (syndrome X) and its fre-

quent sequel, type II diabetes (81–85). Conversely, the

subcutaneous fat stores which would be more gradually

responsive to the measures suggested here – presumably

the ‘gynoid’ depots – are precisely those which have

minimal impact on health (and, if desired, could be

targeted for liposuction).

The ability of hepatocytes to achieve reverse electron

transport, and thus decouple ketogenesis from the meta-

bolic energy needs of hepatocytes, is by no means an

evolutionary fluke. Clearly, ketogenesis is crucial to

meeting the energy needs of the central nervous system

while enabling protein sparing during prolonged fasts;

it would be most counterproductive if sluggish hepato-

cyte metabolism in fasted animals were to impede the

efficiency of ketone generation. The central thesis here

is that it may prove possible – perhaps via pyruvate,

HCA, and carnitine – to amplify reverse electron transport

in hepatocytes, thus substantially uncoupling hepatocyte

oxidative metabolism and promoting the efficient con-

version of portal FFAs to CO2 and heat. In vitro studies, in

which hepatocytes are exposed concurrently to pyruvate,

HCA, carnitine, and FFAs, should readily determine

whether these proposals have validity. In the meantime,

clinical efforts along the lines described in the Appendix

should continue, and attempt to verify not only the

efficacy, but also the safety of these measures.

In regard to safety considerations, it may be noted that

the strategy suggested here utilizes only nutrients, a

natural metabolite, and a food compound (HCA) tradi-

tionally consumed in Indian cuisine – none of which has

shown any evident toxicity in previous clinical experience.

Also, with respect to the increased gallstone formation

commonly observed with rapid-weight-loss diets (86–89),

this appears to be largely attributable to the gallbladder

stasis associated with semi-starvation (89–91); since the

methods proposed here do not require caloric restriction,

there is little reason to suspect that they will induce

gallstones.

APPENDIX

Summary of an informal pilot trial

A short pilot study was conducted to test the impact of a

supplement regimen, in conjunction with dietary and

exercise advice, on fat loss and physique modification

in overweight volunteers. The daily regimen provided the

following, to be consumed in three equal doses: calcium

pyruvate, 12 g; HCA 1.5 g; L-carnitine 250 mg; chromium

(as chromium picolinate) 600 mcg. The supplements

were to be consumed in the morning (prior to exercise

or eating), with lunch, and at bedtime. Participants were

asked to walk at least 20 min each morning, on an empty

stomach; they were asked to walk at a brisk pace at which

they could converse normally. Dietary advice consisted

of recommendations to eat a high-protein, low-fat diet

(30% and 10% of calories, respectively) in an amount that

provided 0.75–1 g protein per pound of lean mass daily

(or 100 g daily for women with lean mass under 100 lb).

These recommendations corresponded to total daily

caloric intakes ranging from 1300–3100 kcal daily, de-

pendent on body size; the average recommended intake

was around 2000 kcal daily. This was to be consumed

in numerous small meals daily, and no calories were to

be ingested in the 3 h prior to bedtime. An ample intake

of water was also suggested, and fiber-rich foods were

recommended.

Body composition was evaluated at baseline and at

weekly intervals thereafter using Futrex 5000, a new infra-

red technique for quantifying the depth of underlying

subcutaneous fat (92,93). All measurements were made

by the junior author (JCG) on the dominant arm, using a

contact point on the anterior aspect of the exterior

midline of the biceps, halfway between the antecubital

fossa and acromion (as recommended by the Futrex

manual.) On each occasion (except the last), measurements

were taken in triplicate and averaged. (Unfortunately,

time constraints prevented triplicate measurements during

the final evaluation. This probably had little impact on

the final results, as JG’s replicate measurements typically

vary by less than 2%). Heights and weights were also

determined, thus enabling calculation of body-mass

indexes (BMIs).

A total of 23 volunteers – the majority Samoan-American

– appeared for enrollment. They were admitted in three

groups on 6/28/97, 7/2/97, and 7/5/97; final evaluation

for all subjects was on 7/26/97. Three subjects did not

return after baseline evaluation, and one subject did

not return for final evaluation. Two subjects refused to

be weighed at baseline (insisting on ‘reporting’ their own

weights) and therefore could not be properly assessed.

One subject developed a rash after three days, and

pyruvate was discontinued. There were thus 16 parti-

cipants who were evaluable. The initial body weights of

these subjects ranged from 69 to 231 kg, with a mean

weight of 117 kg. Percentage body fat ranged, from 26%

to 54%, with a mean value of 41%. The average BMI

was 39.3 (range 26.2–63.7).

Most subjects tolerated the regimen quite well. As

noted, one subject developed a rash and pyruvate dis-

continued. The largest enrolled subject (initial weight

231 kg), who also lost the most weight and fat, had a

prior history of gout, and experienced an attack of gout

during the final week which prevented him from walking.

One subject noted borborygmus and gas.

Most subjects reported feeling warm during the study.



In the first week, three subjects reported sweating and/or

subjective feelings of heat (including a woman who at

baseline had complained that she was always cold). Since

this was thought to be a possible sign of increased

thermogenesis, the other subjects were queried as to

whether they were experiencing sensations of warmth,

and the subjects were virtually unanimous in affirming

this. One subject (again, the largest one) noted profuse

sweating and indicated that he needed to turn a fan on

himself at bedtime to enable himself to get to sleep.

The other virtually unanimous subjective response was

of considerably increased physical energy.

Self-reported compliance with the dietary and exercise

recommendations was excellent in many subjects, but

others confessed to occasional junk-food binges, a failure

to achieve the suggested intake of protein, or sporadic

adherence to morning walking exercise. Self-reported

compliance with the supplement regimen in general

was quite good, although a few subjects noted that they

had missed several doses. Participants were free-living

and, with the exception of a whey protein supplement

provided to several subjects, their food was self-chosen.

Exercise was not monitored. Thus, the conditions of the

study were closer to ‘real world’ application than is the

case in most carefully supervised clinical studies. Further-

more, no subjects were excluded from the final analysis

owing to sporadic (or in a few instances, non-existent)

compliance with either dietary, exercise, or supplemen-

tation recommendations.

Since subjects were enrolled for varying periods of

time (3–4 weeks), results are reported as average weight

loss and average fat loss per week. In the entire group of

16 subjects, average weekly weight loss was 1.5 kg; averageweekly fat loss was 2.3 kg. This evidently implies a weekly

gain of lean mass averaging 0.8 kg.

The largest subject achieved, within 24 days, a weight

loss of 11.8 kg and, remarkably, Futrex analysis indicated

a fat loss of 22.7 kg. If this subject is excluded from

the analysis as atypical, the average weekly weight and

fat losses in the remaining 15 subjects were 1.4 kg and

2.0 kg, respectively.

Since grossly obese subjects have often been noted

to lose significant weight initially when their diet is regu-

lated (preventing binges on favorite. foods), a separate

analysis was made of the five subjects with initial weight

under 200 lb (91 kg). In these subjects, average weekly

weight loss and fat loss averaged 1.3 kg and 1.8 kg re-

spectively – not greatly different from the group as a

whole. The subject with the lowest body weight, as well

as the subject with the lowest initial percentage body

fat, achieved rates of fat loss of 2.0 and 2.7 kg per

week, respectively. Thus, benefit does not appear to be

contingent on severe obesity.

To ascertain the regularity of response, it is appropriate

to note the poorest response in the 16 subjects. A 74-kg

woman lost 3.2 kg of weight and 4.5 kg of fat over four

weeks. During the final week, she had been traveling

to Australia, and had been completely noncompliant with

the diet and exercise recommendations.

It is notable that, in every subject, lean mass increased

during the study. Thus, response was quite different from

that seen during very-low-calorie dieting. The subjective

increase in energy (which helped some subjects comply

with the recommended exercise) and in body warmth, is

also hardly typical of response during calorie deprivation.

Perhaps the most telling indication of the success of

the regimen was the mob scene which greeted the in-

vestigators at the final evaluation – dozens of friends and

relatives of the volunteers had shown up, demanding to

be included in the study!

The authors are acutely aware that a study of longer

duration would have been more meaningful – particularly

since it is important to confirm durability of response to

this regimen. Unfortunately, the businessman sponsoring

the study (not affiliated with Nutrition 21) refused to

provide pyruvate capsules beyond the four-week point,

when he became apprised of the fact that pyruvate had

already been patented for use as a diet aid.

If one assumes that 1 lb of fat corresponds to about

3500 kcal, whereas 1 lb of lean averages 700 kcal, the

average daily calorie deficit was approximately 2370 kcal

(2100 kcal if the heaviest subject is excluded form

analysis). Given the fact that the subjects were not sub-

jected to severe caloric restriction (indeed, a few com-

plained that they were being asked to eat too much!),

and were asked to do only walking exercise of modest

duration, these responses are likely to be unprecedented,

and are strongly suggestive of a dramatic increase in

thermogenesis – a view consistent with the many reports

of heat and sweating.

Even if skeptics were to disregard the Futrex analyses

as unreliable, the average monthly weight loss – approxi-

mately 6.5 kg – is exceptional in the context of a regimen

that does not include severe caloric restriction, draconian

exercise, or drugs.

Although not discussed in the body of this paper, the

nutrient chromium picolinate was included in the supple-

ment regimen. In the two largest controlled studies to

date evaluating the impact of this nutrient on body com-

position in overweight subjects (400–800 mcg chromium

daily), a significant incremental fat loss (relative to placebo)

averaging 0.4 kg per month was observed (94,95). Pre-

sumably, the supplemental chromium may have had an

additive impact on the fat loss achieved during the

present study. However, whether it might also have had

a synergistic interaction with the other compounds

administered (for example, by down-regulating insulin

secretion, allowing glucagon to work more effectively),



obviously cannot be determined from this study, but

requires consideration in future studies.

As a scientific study, the pilot trial described above

has many overt deficiencies. Clearly, confirmatory studies

are urgently needed using double-blind design, a more

accurate technique for body composition assessment

(i.e. immersion densitometry or DEXA), more extended

duration, assessment of blood parameters to monitor

safety, and respiratory analysis or the double-labeled

water technique to quantify metabolic rates and respira-

tory quotients. However, despite the fact that the current

study was virtually an exercise in ‘guerilla nutrition’

conducted not for science per se but to aid in product

development – the results are so striking that they seem

very likely to point the way to a new and important

approach to modification of body composition. Whether

or not the theoretical mechanism suggested in the body

of this paper proves to have validity, the authors are

convinced that the joint administration of pyruvate, HCA,

L-carnitine, and chromium picolinate, in adequate and

appropriate doses, has very considerable potential as a

novel strategy for physique modification. We urge experi-

enced well-trained bariatric scientists (which the authors

cannot claim to be) to attempt replication of methods

described here; frankly, we do not expect properly skep-

tical scientists to believe the remarkable and counter-

intuitive results reported above until they have ‘seen it

with their own eyes’. That being said, we nonetheless

affirm that we have attempted to be scrupulously honest

in collecting, analyzing, and reporting the data from this

informal study.

With regard to safety considerations, it is conceivable

that the rash experienced by one subject reflected a trace

contaminant in the 12 g of pyruvate consumed daily.

An allergic reaction to the Garcinia extract used (50%

HCA as the calcium salt) is also a possibility, but seems

unlikely since the rash cleared while Garcinia intake

continued. The flare-up of gout experienced by one

subject might be attributable to ketosis, which reduces

renal clearance of uric acid (96,97); the high protein

intake might also have been a contributory factor. No

subjects complained of abdominal distress suggestive of

gallstones.

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