Annu. Rev. Nutr. 2006.26:1-22. Downloaded from arjournals.annualreviews.

by CAPES on 04/24/08. For personal use only.
June 12, 2006
Annual Reviews

4 Jul 2006 17:32 AR ANRV282-NU26-01.tex XMLPublishSM (2004/02/24) P1: IKH

Annu. Rev. Nutr. 2006. 26:1–22
doi: 10.1146/annurev.nutr.26.061505.111258
Copyright c 2006 by Annual Reviews. All rights reserved
First published online as a Review in Advance on May 9, 2006

George F. Cahill, Jr.∗
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115;

Key Words starvation, ketosis, β-hydroxybutyrate, brain
Annu. Rev. Nutr. 2006.26:1-22. Downloaded from

■ Abstract This article, which is partly biographical and partly scientific, summa-
rizes a life in academic medicine. It relates my progress from benchside to bedside
and then to academic and research administration, and concludes with the teach-
ing of human biology to college undergraduates. My experience as an intern (anno
by CAPES on 04/24/08. For personal use only.

1953) treating a youngster in diabetic ketoacidosis underscored our ignorance of
the controls in human fuel metabolism. Circulating free fatty acids were then un-
known, insulin could not be measured in biologic fluids, and β-hydroxybutyric acid,
which was difficult to measure, was considered by many a metabolic poison. The
central role of insulin and the metabolism of free fatty acids, glycerol, glucose, lac-
tate, and pyruvate, combined with indirect calorimetry, needed characterization in a
near-steady state, namely prolonged starvation. This is the main topic of this chap-
ter. Due to its use by brain, D-β-hydroxybutyric acid not only has permitted man
to survive prolonged starvation, but also may have therapeutic potential owing to its
greater efficiency in providing cellular energy in ischemic states such as stroke, my-
ocardial insufficiency, neonatal stress, genetic mitochondrial problems, and physical

THE EARLY YEARS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
ADIPOSE TISSUE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
THE BRIGHAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
STUDIES ON STARVATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
β-HYDROXYBUTYRATE AND ENERGY PRODUCTION . . . . . . . . . . . . . . . . . . . 10
β-HYDROXYBUTYRATE: THE MOST EFFICIENT FUEL . . . . . . . . . . . . . . . . . . . 15
UNDERGRADUATE TEACHING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
RETIREMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Send correspondence to G. Cahill at P.O. Box 367, Stoddard, New Hampshire 03464-0367.

0199-9885/06/0821-0001$20.00 1

The most significant figure in my life was my father. eventually six in all.26:1-22. with a large number of patients from the business. my maternal grandparents. Nutr. I enlisted in the Navy as Hospital Corpsman Second Class at age 17. and I ended up chairing the Chem-Physics club at the school. Yale was one party with a few academics thrown in. or to the home of one of his Columbia colleagues. The bottom line is that our life was very active. who after his Sunday rounds at the Columbia/Presbyterian Hospital frequently took me to the Natural History or Metropolitan museums. until one evening when my father said there would be no more German talk. County Clare. and sang soprano through my second year! Biology. My first three years of educational instruction were given partly in German by a Fräulein. After I completed boot camp in Sampson. I was sent for more than a year to the Oakland. He did well academically and was accepted as an intern in the postgraduate surgical section at New York’s Bellevue Hospital. Downloaded from arjournals. My father went to Hillhouse High in New Haven. Both grandfathers died in their nineties after working during World War II into their late seventies in factories in New Haven. second-generation American family. He supported himself as a night railroad express agent several blocks from New Haven Hospital. and mathematics were my love. married in 1916. Near the same time. age 16. Squier as head of Urology at Columbia and became one of New York’s best-known commanding officer of Field Hospital #8. My wife. Columbia P&S was a turning point. particularly in academics. Rev. in about 1870. Instead. 1927. the youngest and second smallest in the ninth grade. by CAPES on 04/24/08.annualreviews. I entered Yale in 1944. newly privileged. which was full of the Okinawa wounded. and then Corps School in San Diego. and the above personal information illustrates a classic self-made. I had a grand time—including fraternities. Bentley Squier at Columbia College of Physicians and Surgeons. went to France in 1917. I graduated in 1953. and political arenas. 2006. however. For personal use only. I returned to Yale as a premed student and then went to Columbia College of Physicians and Surgeons (P&S). Those in our home on Park Avenue in New York City had a strong work ethic. George Sr. to the Aquarium or the Bronx Zoo. academic. chemistry. and at age 16 was taken into the class of 1911 at Yale Medical School. New York. both physically and intellectually. The relevant role of George Sr. Sally. I was shipped off to the Hotchkiss School in Connecticut at age 12. Connecticut. After his return to Bellevue. who lived with us. He eventually served and presided at the major national and international urologic organizations. he joined the Urologic Service of J. thanks to Hitler. and was then finally able to compete athletically. athletics. 4 Jul 2006 17:32 AR ANRV282-NU26-01. the bomb saved me from joining a Marine platoon in Camp Pendleton to invade Japan. Germany. a hospital originally operated by the French but taken over by Americans after we officially entered the fray. and I married in 1949 and began to have children. my youth and smaller size limited my athletic career until my senior year. came from Schwaben. where he continued to work until his death in 1959 due to complications from a perforated duodenal ulcer. California. He succeeded Dr.tex XMLPublishSM (2004/02/24) P1: IKH 2 CAHILL THE EARLY YEARS The Cahill grandparents came from the west of Ireland. Naval Hospital. and many . theatrical. and ended up as Annu. I was born in the city on July 7. the Wagners.

and one night. I was assigned to work with an English research fellow. I responded to an invitation for students who were interested in research to meet with Dr. VIA BIOCHEMISTRY The name Thorn kept appearing in the endocrine literature and. With another student.26:1-22. with an emphasis on pathophysiology and biochemistry. One of our former fellows. He was my early education and family life! The GI Bill helped me meet the Yale and P&S expenses. and brilliant. 2006. I already had some exposure from my father. My senior resident was a German Swiss. Downloaded from arjournals. nephew of geneticist Sir Archibald Garrod. Renold and I discussed the how and why of ketosis through the night. And. The Brigham was an exciting hotbed of medical research into areas including renal dialysis. . heart valve repair. we char- acterized the acute effects of glucocorticoids on renal function in adrenalectomized dogs (25). Robert Loeb. 4 Jul 2006 17:32 AR ANRV282-NU26-01. meaning the physiologic response is not only a function of insulin level but also the rate at which the level is achieved. 57). Dr. Albert Renold. eager. Every patient was discussed in depth. Rev. In my third year. I applied to the Peter Bent Brigham Hospital in Boston. It produced urine for six months. My first two years at Columbia P&S were inter- esting but not very challenging. particularly of the adrenal. more interestingly. and he was discharged a few days later. Oliver Garrod. the higher insulin level needed to be achieved rapidly. hypotensive. was a high school dropout who lived in poverty with an alcoholic family. I befriended him and saw him on numerous occasions for about ten years. and had dry skin with poor turgor: classical diabetic coma.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 3 permanent friendships—but not much intellectual growth in comparison with my experience at Hotchkiss. ENDOCRINOLOGY AND METABOLISM by CAPES on 04/24/08. This led me into reading about the adrenal. The lad. He was also the first on the East Coast to successfully remove a pheochromocytoma. chairman of Medicine. we took care of a moribund. One of my first patients as an intern (“Medical House Officer”) in Medicine was a Peruvian physician who had a kidney implanted into his right groin by Dr. was Physician-in-Chief. We found that establishing a fixed insulin level to maintain a normal fasting glucose concentration was inadequate to allow the body to handle a glucose load. So off we went to Boston with our two kids. because I had grown up in New York as well as attended medical school there. particularly with the sweet smell of acetone. The medical students were plentiful. He served as a volunteer for a number of studies on insulin/glucose relationships. Nutr. He awakened after we administered appropriate fluids and intravenous insulin. For personal use only. Thorn. where George W. namely dinsulin /dt. long before immunosuppression was in use (74. renal transplantation. p. unconscious young lad brought in by the Boston Police. while on Emergency Ward duty. David Hume. But I can thank prostate surgery for financially supporting Annu.annualreviews. who operated on adrenal tumors and hyperplasias with endocrine abnormalities. and endocrinology. the Hersey Professor of the Theory and Practice of Physic. an Irish American from the Mission Hill District of Boston.

Downloaded from arjournals. By the early 1960s. and the major effort at the time was devoted to studies on adipose tissue using the rat epididymal fat pad. and CO2 were all diminished in the diabetic. But all of these studies suggested that the role of insulin in fasting is very important. we found a reciprocal increase by CAPES on 04/24/08. Prior to this time. many years later studied in depth this approach in the treatment of very labile type 1 diabetics and found that very rapid intravenous pulses of insulin markedly improve glucose homeostasis for days to weeks (1). Hausberger at Philadelphia. including human serum. Also. After a second clinical year. who had moved several blocks to the Baker (later the Joslin) laboratories at the New England Deaconess Hospital. Many small points were clarified regarding adipose tissue. This was just the time that Eugene Knox demonstrated the adaptability of hepatic tryptophan oxidase to dietary tryptophan levels. It covered the adipose literature up to 1966 and contained more than 4300 references (56). I returned to the Brigham for another clinical year and then joined Renold. ADIPOSE TISSUE After two years in the Hastings lab. Spain. Renold had spent two years in the Department of Biological Chemistry with Prof. The Brigham had and .annualreviews. and found glucose metabolism to have an overall Km about 5 “glucokinase” that was controlled by insulin (10). an erroneous concept emphasized at Harvard by Professor Otto Folin. which. Baird Hastings prior to his Brigham senior residency. Fructose uptake was similar. many from Europe (particularly Switzerland). I joined the Hastings laboratory. fat. with James Ashmore. Thorn’s Department of Medicine. He had a small group of fellows. labeled glucose conversion into glyco- gen. but academically under the aegis of Harvard Medical School via Dr. glucokinase. by the way. 2006. Rev. was and continues today to be a part of the Joslin Foundation. The en- zyme. and its decrease in diabetes were soon characterized by Sidney Weinhouse in Philadelphia and Alberto Sols in Madrid.tex XMLPublishSM (2004/02/24) P1: IKH 4 CAHILL Thomas Aoki. who had preceded Professor Hastings as chairman of Biological Chemistry. The exquisite sensitivity of the pad to insulin. The finding that this was not due to cell permeability suggested the presence of a specific hepatic Annu. perhaps as important as its role in the fed state. 4 Jul 2006 17:32 AR ANRV282-NU26-01. was used by Renold and colleagues as an assay for circulating insulin in biological fluids. a preparation originally characterized by E. Wertheimer and colleagues in Israel and F. enzyme activities were thought to be relatively stable. however. another fellow in the lab at the time. A. Renold and I assembled what was then known about adipose tissue in the Handbook of Physiology for the American Physiological Society. as quantified by increased glucose oxidation to CO2 . Nutr. such as the release of free glycerol with the fatty acids mobilized during fasting or epinephrine stimula- tion (42). In contrast to muscle. For personal use only. glucose permeated the liver cell wall equally in normal and diabetic patients (9). I was in charge of the Brigham Endocrine-Metabolic Unit in addition to my research efforts with Renold at the Baker lab. in glucose-6-phosphatase activity in the diabetic liver (3). Insulin therapy corrected the deficiency.26:1-22. studying carbo- hydrate metabolism using C14 in liver slices from normal and alloxan diabetic rats.

2006. I should add that my original plan was to spend a year in medicine and then to move on to Dr. The Renold tutelage. and thanks to the small size of the Brigham. except for many collaborative activities with the Brigham surgeons. which also helped greatly. They were slightly more efficient. and the two years in biochemistry took care of any future surgical career. There were only 6 surgical and 12 medical interns. with an annual budget of well over $20 million. We frequently also came early to hear the surgical cases. STUDIES ON STARVATION In 1965. now headed by C. likewise.26:1-22. The central role of insulin in controlling the fed state had been well characterized. immunoassays had been devised for many hormones. for 30 days and nights (4). . the diabetic youngster. The Baker lab has grown into the prestigious Joslin Research The Department of Surgery at the Brigham. and its role in fasting needed clarification. in keeping with the concept of James Neel (at Michigan) that type 2 diabetes may have been an evolutionary selective advantage in a starving population. insulin. under the direction of Francis D. He was a world leader. Rev. We also fasted two type 2 diabetics. Levanzin. (Franny) Moore. Ronald Kahn. who differed from the normals by better nitrogen conservation. we had help. would stay over. the medical and surgical staffs were closely intertwined. although many surgeons. leaving me in charge of the Joslin labs. Nutr. 82). The first half hour was pure surgery. By then. the next full hour was devoted to combined medical/surgical. we enlisted six divinity students to fast for eight days and studied the levels of every metabolic substrate and hormone that we could measure (11). the medical house officers attended and even participated in some of the major surgical procedures.annualreviews. Renold had returned to Geneva in 1962 and founded a major research team focused on all aspects of diabetes. Mr. glucagon. Part of this collegiality was generated at Friday’s Grand Rounds. particularly cardiovascular surgeries. when we medical types were overloaded. and growth hormone in particular. Downloaded from arjournals.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 5 continues to have a Clinical Research Center supported by National Institutes of Health (NIH) funds. THE BRIGHAM Annu. Stuart Soeldner (69) at the Baker laboratory devised an exquisitely accurate and sensitive double- antibody immunoassay for insulin. Essentially. an accurate enzymatic analysis of the ketoacids was designed by Derek Williamson in Sir Hans Krebs’s lab (59. For personal use only. were too busy and. Likewise. we repeated and expanded the 1911 classical study of starvation by Benedict. and this allowed us to characterize the central role that low levels of insulin play in controlling fuel metabolism in starvation. and more than once I helped sew up patients in the ER when the surgeons by CAPES on 04/24/08. and the final half hour to medical alone. focused on the metabolic alterations in surgery and trauma. 4 Jul 2006 17:32 AR ANRV282-NU26-01. who fasted a Maltese. Moore’s Department of Surgery. junior and senior. Also.

26:1-22. along with many succeeding fellows. 55). as we expected. namely muscle. For personal use only. Oliver Owen (29. and valine. Owen continued his studies after his move to Temple (24. The . some 100 to 150 grams/ six-week starvation study (Figures 1 and 2). There were also collaborations with other groups. and catheterization of the Annu. allowed us to piece together the interplay of hormones and substrates in star- vation. isoleucine. Dr. par- ticularly in a primitive environment. who knew of our fasting work. joined our team and launched a series of studies lasting the next five years or so at the Brigham. then on liver and kidney (49). Nutr. such as George Reichard’s team at the Lankenau Institute in Philadelphia (55).org jugular. Muscle nitrogen is probably the determinant of long-term survival in man. mainly alanine (Figures 4 and 5). Guillermo Herrera. Thus. a very bright and industrious Hopkins Medical Resident. it became evident that the fuel substrate for brain could not continue to be glucose since gluconeogenesis from protein would consume so much muscle that long- term viability would be dramatically decreased (6). Aldo Rossini. Many other fellows helped fill out the overall scheme in complementary metabolic studies in tissues in vitro and in rodents and dogs. Total splanchnic glucose production in several weeks’ starvation amounts to approxi- mately 80 grams daily. brain fuel.annualreviews. Urinary nitrogen excretion fell to 4–5 grams/day. 20 grams from fat-derived glycerol. Yet there is still significant brain metabolism of glucose (Figure 3). About two fifths of fatty acid metabolism in the whole body is via hepatic ketogenesis. are metabolized in situ in muscle and the nitrogen re- leased into the bloodstream primarily as glutamine (44) and alanine (15–18). we Homo sapiens might not be here! Oliver Owen’s data on brain (50). an obese person could survive much longer. 4 Jul 2006 17:32 AR ANRV282-NU26-01. Three very intelligent obese subjects were selected for a five. Hepatic glycogen contribution to blood glucose is essentially zero by the second or third day of starvation. a normal adult human could survive two months of starvation. 51.tex XMLPublishSM (2004/02/24) P1: IKH 6 CAHILL Therapeutic fasting of obese subjects was in vogue in the 1950s and 1960s. About 10–11 grams/day come from glucose synthesis from ketone bodies. 35–40 grams from recycled lactate and pyruvate. One has to turn first to the major nitrogen pool. and the remaining 15–20 grams from protein-derived amino acids. Neil Ruderman. and Thomas Pozefsky’s on muscle (53). particularly Philip Felig. 2006. The next question to be answered is how the levels of the above substrates are controlled. markedly diminishing the need for muscle proteolysis to provide gluconeogenic precursors (Figure 3). to name two). Were it not for the β-hydroxybutyrate and acetoacetate providing by CAPES on 04/24/08. Downloaded from arjournals. However. the human studies quantifying the flux of numerous metabolites through various organs dur- ing starvation summarize in simple form these interrelationships (Figure 4). In an informal conversation with Rachmiel Levine. 48). Thomas Aoki. leucine. and several from the surgical staff (Fred Morgan and Murray Brennan. showed some two thirds of brain fuel consumption to be D-β-hydroxybutyrate and acetoacetate. The first question related to brain substrate utilization. The branched-chain amino acids. At about the same time. The team also included Errol Marliss. High points are the significant metabolism of β-hydroxybutyrate and acetoacetate by brain and their production in liver. Rev.

2006. 4 Jul 2006 17:32 AR ANRV282-NU26-01. to maintain extracel- lular volume.26:1-22. (b) recycled lactate and pyruvate (the Cori cycle).org by CAPES on 04/24/08. as in Figure 5.annualreviews. 35) (Fig- ure 5). Nutr.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 7 Annu. mainly sodium. glutamine is mainly metabolized by kidney to produce ammonium ions and the remaining carbon goes to glucose via the gluconeogenic pathway (27. Rev. Downloaded from arjournals.. The remaining three fifths is made by liver from (a) alanine coming from muscle and the nonhepatic splanchnic bed. Figure 1 The five metabolic stages between the postabsorptive state and the near-steady state of prolonged starvation (62). (d) a small amount from β-hydroxybutyrate to acetoacetate to acetone to propanediol to pyruvate to glucose. (c) glycerol from adipose lipolysis.g. For personal use only. e. as mentioned above. It should also be pointed out that ammonia excretion saves calories . The kidneys in starvation produce about two fifths of new glucose. and finally. The urinary ammonium ion is excreted with β-hydroxybutyrate and acetoacetate to maintain acid-base homeostasis and cations. from red blood cells and renal medulla.

tex XMLPublishSM (2004/02/24) P1: IKH 8 CAHILL Annu. Figure 2 Concentrations of ketone bodies and plasma free fatty acids (FFA) in transition from the postabsorptive state to 4–6 weeks of starvation in a large number of by CAPES on 04/24/08.annualreviews. E. Downloaded from arjournals. O. Data courtesy of Dr.26:1-22. male and female. Rev. 4 Jul 2006 17:32 AR ANRV282-NU26-01. For personal use only. . Nutr. Note the more than three orders of magnitude change in β-hydroxybutyrate and the doubling of FFA. Owen. 2006.

but proving the point is difficult as well as experimentally difficult and ethically questionable.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 9 Brain Fuel FED STARVATION 100% GLUCOSE 80% Annu. 2006. trapping . i. two high-energy phosphates per urea nitrogen. otherwise needed for hepatic urea synthesis. Nutr. For personal use only. Rev.. What controls glutamine levels? Acid-base homeostasis has been shown by administration of sodium bicarbonate to diminish urinary ammonium and total nitrogen excretion accordingly in fasting subjects (28. Conversely. 49). Downloaded from 60% by CAPES on 04/24/08. 4 Jul 2006 17:32 AR ANRV282-NU26-01.26:1-22. 51). Many studies suggest human brain cells can survive with little to no glucose.e. GLUCOSE β-HYDROXY- 40% BUTYRATE 20% ACETOACETATE 0% Figure 3 Brain substrate utilization in three fasting obese volunteers after several weeks of starvation (48.annualreviews.

the latter being quantitatively incorpo- by CAPES on 04/24/08. 2006. Many studies have shown re- versal of hypoglycemic signs and symptoms by ketone bodies. Both in the lab and in the clinic. a decrease— . Nutr. P. 81). although this last point is not accepted by all. Downloaded from arjournals. I turn to the question of what controls hepatic glucose production. For personal use only. (66). 4 Jul 2006 17:32 AR ANRV282-NU26-01. 52). and some changes in potentially atherogenic blood lipids. How does the brain function using mainly β-hydroxybutyrate and acetoacetate? Intellect-wise it is indistinguishable from glucose. which suggests a fine homeostatic control of blood glutamine levels. the regulator being insulin concentration and its subsequent metabolic effect (8) (Figure 4). my colleague Richard (Bud) Veech. (35) and Sato et al. about one third of the children with multidrug-resistant epilepsy improve dramatically on a strict ketogenic diet. 26). some changes do occur. Annu. the liver in starvation is wide open. Kashiwaya et al. Yet. as in patients with anorexia nervosa who eat some 100 grams or less of carbohydrate daily (23).26:1-22. and patients may experience gastrointestinal problems as well as a degree of osteoporo- sis. Gonadotrophins decrease. Rev. renal glucose production appears to surpass that which can be explained by glutamine consumption alone. As originally championed by Felig (16).tex XMLPublishSM (2004/02/24) P1: IKH 10 CAHILL glutamine by administration of phenylacetate to fasting subjects increased urinary nitrogen excretion by the amount excreted as phenylacetylglutamine (51). administration of alanine results in a rapidly increased glucose synthesis. delayed growth. there are metabolic alterations. Also. What controls ketogenesis? First. Elevated levels of β-hydroxybutyrate inhibit adipose release of free fatty acids (73. and the remainder experience little or no effect. The problem is that the diet has poor palatability. β-HYDROXYBUTYRATE AND ENERGY PRODUCTION In 1995. but insulin is necessary for this effect. delayed puberty. Adherence to the diet is clinically difficult (61). as is well known in the world of epilepsy. Flatt (21) has suggested that mitochondrial adinosine triphosphate (ATP) produced by the partial oxidation of fatty acids to β- hydroxybutyrate and acetoacetate provides the major energy for liver metabolism and thereby reaches an upper limit approximating that achieved in diabetic ke- toacidosis (40). and his associates at the NIH. so to speak. rated into glucose by the liver.annualreviews. the syndrome of hypoketonemic hypoglycemia in children is associated with low levels of circu- lating alanine and is corrected by alanine administration (31. reported that the working perfused rat heart showed an increase in work output and a decrease—yes. On the other hand. but these also decrease in other caloric deficits without elevated ketone levels. Next. It appears simply to be the rate of release of alanine from muscle as reflected by its blood concentration (18). As popularized by the Hop- kins group of John Freeman and Ellen Vining and associates (22. PhD. However. MD. another one third improve to some extent. It thus appears that the blood glucose level in starvation is controlled by muscle proteolysis. the accelerated adipose tissue lipolysis pro- duces increased fatty acids and glycerol.

by displacing glucose as its major fuel. This is the only example of a nonprotein ion channel so far reported. This is in contrast to the two other fundamental archaeal energy stores. Measuring enzyme activities is only a small component of the picture. I should point out that I have been unable to find evidence of triglyceride in prokaryotes! Returning to fasting man. Richard Strohman used the work of Veech and colleagues (35. Proterozoic. 79. particularly with bipedalism. some 7 mya. 66. particularly in reproduction. therefore having very little osmotic effect. It is also present in low concentrations in blood serum.D. Bipedalism necessitated narrowing of the pelvic canal . coliforms are an exception. polypyrophosphate (38) and various polysaccharides (14). so are the genetic controls of the enzymes. In some proto- zoans.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 11 in oxygen consumption when β-hydroxybutyrate was added to the glucose in the medium. brain use of βOHB. Other secondary adaptations had to be made. For personal use only. it has permitted brain to become the most significant component in human evolution. but apparently not for energy. with 2–4 grams of water stored in cells along with each gram of glycogen (19). sapiens and the recent antecedents such as neanderthalensis. The data demonstrated that the increased efficiency was the result of the widening mitochondrial substrate ratio of NADH and NAD+ between complex 1 and complex 2. Nutr. which suggests it has been around for well over 2–3 billion years. and Palaeozoic eras. and the proteome.26:1-22. 2006. Polypyrophosphate for energy storage disappeared with the prokaryotes. in one case. One can talk of the genome. The mega brain of H. a component of a Ca2+ channel (57). 4 Jul 2006 17:32 AR ANRV282-NU26-01. Rev. A recent book by E. we have retained poly-βOHB. as the hominoids became hominids. Small changes in transcription and translation in enzyme protein synthesis and thus in enzyme levels may be functionally unimportant in overall metabolic control. has allowed man to survive lengthy periods of starvation. erectus. Even archaea use it for energy storage. It is a component of cell walls and. Strohman has applied the term “strength control” to this science (71). Poly-βOHB is stored as several large granules in the cytoplasm. underscored the fundamental role of nonequilibrium thermodynamics in living systems. Downloaded from arjournals. This observation stemmed from an immense amount of laboratory work to measure numerous metabolic intermediates. Both of these require much hydration. It is possible that its selection was aided by the periods of low environmental oxygen that occurred during the Archaean. 80) to illustrate the essentiality of determining numerous substrate concentrations involved in enzymatic reactions controlled by thermodynamic principles to understand fluxes in complex metabolic little. The net effect is a greater potential for ATP production. But more importantly. the basis of metabolic homeostasis. Schneider and D. the transcriptome. and stepping back a Annu. This brings us to the evolutionary history of β-hydroxybutyrate (βOHB) and the role of various energy sources required for life. and habilis posed a problem in getting the big head through the pelvic canal. up to 90% of dry weight is poly-βOHB. and altered levels have been reported in diabetic animals (58). Most bacteria use poly-β- hydroxybutyrate as an energy store. but the control is in the metabolome. However. Sagan (68) has by CAPES on 04/24/08.

13. Also. Not shown is the accelerated ketosis in fasting pregnant or lactating women or in any subject with marked renal glucosuria requiring increased gluconeogenesis. we are the only pri- mate born fat. Rev. is the metabolism of the human newborn.g. 4 Jul 2006 17:32 AR ANRV282-NU26-01.26:1-22.e. We are also the only primate with significant neonatal brain injury (20) due to extreme sensitivity to hypoxia/ischemia (78). which is essentially ketotic.tex XMLPublishSM (2004/02/24) P1: IKH 12 CAHILL s yr 6 8 6- β-Hydroxybutyrate (mM) Adults n re 5 ild s Ch yr 4 4 2- n n or re wb nt ild 3 fa Ch Ne In 2 Annu. We are the only primate born facing backward and. Again. Nutr. and con- centrations of βOHB may rise to 2–3 mM. 59. 30. Fitting in with this pattern is maternal colostrum. probably to furnish the caloric bank for our big brains. deer versus turtles. The newborn human brain consumes 60%–70% of total metabolism at birth. Blood glucose levels fall strikingly in the neonate. during which time ketosis disappears. for optimal 1 0 by CAPES on 04/24/08. whereas limbs far apart result in waddling. or with genetic renal glucosuria or chemical inhibition of tubular reabsorption of glucose (phlorizin administration).. but little lactose.annualreviews. 54. starting man’s entry into society on an Atkins diet (Figure 6)! Lactose gradually increases during the first two to three days of lactation (46). nearly half via β-hydroxybutyrate. as in type 1 diabetes (40). It contains much triglyceride and protein.. more importantly. this is a penalty for having a big brain! . Downloaded from arjournals. when the renal threshold is surpassed. Not well known. again. For personal use only. born obese. i. greyhounds versus bulldogs. 2006. 66). And. Speed necessitates limbs close together. 0 4 8 12 16 20 24 2 3 4 5 6 Hours Days Figure 6 Levels of β-hydroxybutyrate in starving subjects of different ages (5. Obstetric problems in primates other than humans are essentially unknown (60). however. e. humans are born a few months pre- mature compared with our primate cousins. pheasants versus ducks.

Nutr. lactation necessitates increased gluconeogenesis. βOHB plays a central role in prolonged starvation in man.5 mM while the bear is starving in its den (70). Was the bear ketotic during that period? No. already on a ketogenic diet from its rumen. achieve levels over 5 mM. as far as we know.26:1-22. For personal use only. This energy importance of colostrum is sup- plemented by its immunoglobulins. as in the newborn. similarly induces ketosis in both man and experimental animals. This includes several cetaceans with 20. the brain size of adult H. is just another glucose-consuming tissue like brain. Ralph Nelson at the University of Illinois has studied renal function in the black bear in winter sleep and has found that the level of βOHB remains below Annu.annualreviews. where the immune defense provided by colostrum is critically important for survival. and nursing mothers who are fasting experience increased ketosis. The larger the brain/body ratio. Although I have no data. The reason is that glycerol from adipose lipolysis is more than adequate to provide glucogenic substrate for hep- atic gluconeogenesis. similar to eating small amounts of carbohydrate. if determined. The blockade of tubular reabsorption of glucose in the kidney by phlorizin. the more rapidly the ke- tosis develops. Any extra demand for glucose synthesis augments hepatic gluco- neogenesis. if at all. 4 Jul 2006 17:32 AR ANRV282-NU26-01. However. which tragically can occur in prolonged population starving or more rapidly in diabetic ketoacidosis. 5-month winter sleep. Any animal whose brain accounts for less than 5% of total metabolism need not and does not get ketotic during starvation (ruminants are an exception.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 13 Several reports have noted that infants raised on the breast from birth are brighter than those placed on formula (43). by a local black bear that had emerged from its den after a 4. ketogenesis. prolonged severe ketosis in a starving female may terminate pregnancy. Levels of 5 mM or higher can be achieved in children in two to three days of starvation (Figure 5). and pari passu. and. sapiens is poorly. related to the size of the remainder of the body! There are several exceptions to the genesis of ketosis in man described 40-pound brains by CAPES on 04/24/08. Rev. The farmer finds his best milk-producer staggering in the pasture. Except for some small rodents that can achieve βOHB levels of 2–3 mM on starvation. the ideal candidate for long-term starvation survival would seem to be a sumo wrestler or an overweight six-foot-tall Polynesian male or female in whom brain would be some 10% of total metabolism. vide infra). and multiton bodies that eat annually for a period of only several weeks and yet have ample glucose for brain owing to a plentiful supply of glycerol from their adipose tissue. The same holds true for the pregnant woman. Apparently. the adult average being between 4 mM and 7 mM after two weeks fasting. most rodents have levels that remain at less than 1 mM. calorically speaking. To summarize where we are so far. In the same vein. The increased glycerol from adipose lipolysis would increase hepatic glucogenesis and spare muscle nitrogen accord- ingly. Downloaded from arjournals. since the conceptus. 0. and only humans. How about other long-term starvers? Recently our bird feeder was destroyed. but it is not as important as in some of our domesticated animals. particularly the newborn foal. suffering from . pro- ducing marked glucosuria. This same concept holds in the ruminant. as it is every year.

1 mM). Therapy is a bolus of 50% glucose. . but more practical is simply a molasses “lick. 2006. 63). For personal use only.0 mM βOHB and 3. Glucose administration to fasting normals reverses starvation metabolism rapidly. Nutr.5 mM sociated with βOHB of approximately 1 mM. An approximation for clinical use is that if a diet contains over 100 grams carbohydrate. 4 Jul 2006 17:32 AR ANRV282-NU26-01.annualreviews. particularly nitrogen loss (Figures 7a and 7b). In vitro studies using brain slices show the priority of CNS usage of βOHB over glucose (33. Even a small amount such as 7.5 grams decreases ketoacid and ammonia nitrogen excretion (65). ketogenesis begins. As one decreases dietary carbohydrate. two thirds of brain’s metabolic substrate is βOHB. An anthropo- logic extrapolation would suggest that a few berries or a carbohydrate-containing by CAPES on 04/24/08.” Also. Downloaded from arjournals. twinning in sheep by adding the glucose needs for two concepti to the otherwise small glucose need by brain necessitates increased glu- coneogenesis and concomitant increased ketosis. there is no ketosis (<0.26:1-22. Rev. but wide variations exist between people. With 7.tex XMLPublishSM (2004/02/24) P1: IKH 14 CAHILL hypoglycemia. It appears that one can roughly use the relative molar con- centrations of βOHB and glucose to know the relative brain metabolism of the two. Figure 7 Inhibition of starvation metabolism by administration of 150 grams of glucose daily for seven days either before a fast (Figure 7a) or following three weeks of starvation (Figure 7b) (horizontal line at top of each figure is glucose infusion) (2). Glucose intake (“carbs”) of 20–40 grams is as- Annu.

Nutr. similar to the perfused heart. For personal use only.17 ∗ National Bureau of Standards. protein intake plays a very large role. Again.72 Acetic acid 3. 4 Jul 2006 17:32 AR ANRV282-NU26-01. to pyruvate. caloric homeostasis in a 70-kg man on protein alone is incompatible with life since the maximum rate of urea synthesis is insufficient to provide even basal calories. the degree of ketosis in man on a high-protein. Absent carbohydrate is similar to total starvation. and particularly to free fatty acids (39). high-fat diet. However. and this certainly is a very significant component in the treatment of by CAPES on 04/24/08.48 Pyruvic acid 3. 101). One then has to consider β-hydroxybutyrate as a unique nutritional compound (Table 1). . 2006. showed that bull sperm motility was increased in vitro by β-hydroxybutyrate as compared with 15 other substrates but with a decrease in oxygen consumption. High protein. as well as carbohydrate. it is an archaic molecule.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 15 TABLE 1 Metabolic fuels∗ Substrate Kcal/g Free fatty acids 9.L. Veech has summarized in a recent publication (79) the biochemical mechanisms whereby β-hydroxybutyric acid is the most efficient fuel per molecule of oxygen con- sumed when compared to glucose. or 250–325 grams of protein (64).1 It has equally balanced hydrophilic and hydrophobic characteristics. in the root nibbled intermittently by a cruising hunter-gatherer might be critical for long- term survival. The Arctic explorer Stefansson as well as others eating pure meat without the blubber learned this only too well. Henry Lardy (41). The biochemical and biophysical discussion is beyond the scope of this paper. Also.26:1-22. Rev. addressed this question in 2001 (80) and again more recently in 2004 (79).31 β-hydroxybutyric acid 4. Downloaded from arjournals. p. A more simplistic paper for physicians was also published (12). children with epilepsy by the ketogenic diet. about 1000–1300 Kcal/day. has to be avoided. Annu. β-HYDROXYBUTYRATE: THE MOST EFFICIENT FUEL Veech and colleagues discovered that administering β-hydroxybutyrate to the per- fused rat heart in place of glucose increased work output but decreased oxygen consumption (35). Protein poisoning in Arctic explorers is well described by McKinlay in his report on an Arctic tragedy (45.annualreviews. One can consider 1 gram of protein to produce about a half gram of glucose. However. One 1 R. namely the diet of the Inuit. Does it have any therapeutic value as either a nutraceutical or a pharmaceutical agent? Veech et al. is intermediate thanks to the protein (32).69 Glucose 3. and therefore is neither fat nor carbohydrate.

Veech and K. any cell challenged by low oxygen availability or by a toxin inter- fering with mitochondrial function should benefit by utilizing β-hydroxybutyrate in preference to any other substrate. and most importantly. Professor Stanton New- man of London (47) has reviewed the clinical and pathologic data. or fatty acids. In a very simple experiment. If it takes 125–150 grams/day of βOHB to bring an adult to 5 mM. This brings up a number of possibilities for its potential therapeutic uses. Experimental animal data indicate increased survival of brain cells is a high probability with 5 mM β-hydroxybutyrate in the circulation. 2006. . It readily crosses the placenta.L. Nutr. Likewise. As of this writing. mice given β-hydroxybutyrate exposed to 4% by CAPES on 04/24/08. may have a dramatic reversal of their nervous system problems and. though effective. attempts are being made to synthesize esters of β-hydroxybutyrate that are orally acceptable and metabolizable to provide sufficient therapeutic levels in the circulation. Ke- tosis. Clarke. 77). is unpalatable and has some metabolic adver- sities. Next. hereditary or acquired. as described above. more interestingly. subsequently are able to improve in psychological tests (R. 72). has a major role in drug-resistant epilepsy. deal with the sodium overload.tex XMLPublishSM (2004/02/24) P1: IKH 16 CAHILL can posit a number of uses. For personal use only. The sodium salt has been given to children without apparent problems. particularly those put on a bypass pump machine. Essentially. 75 grams or so is required for a child. As mentioned above. Downloaded from arjournals. particularly if small for gestational age. However. If given as the sodium salt. A significant clinical improvement has been shown in patients with Parkinson’s disease placed on a severely carbohydrate-deficient diet (76. but the amount needed to get the blood level into the therapeutic range for epileptic children challenges the capacity to excrete alkaline urine as well as Annu. it causes metabolic alkalosis. including glucose. the fact that nature delayed the synthesis of adequate lactose for the first day or so suggests βOHB might be of help in any newborn. improvement of cardiac function. 75). in some (75). the agent being infused into the mother.annualreviews.26:1-22. 4 Jul 2006 17:32 AR ANRV282-NU26-01. oxygen survived longer (37. infants with hereditary deficiencies in fat metabolism given much smaller amounts appear to tolerate the excess alkali. it could have numerous applications. neurons in models of Alzheimer’s and Parkinson’s disease survive better with β-hydroxybutyrate in the system (36). But if βOHB increases the capacity of oxygen-deprived or otherwise ATP-deficient states as in mitochondrial deficien- cies. which show nu- merous microemboli in brain cortex. Recent studies have shown that rats fatigued on an exercise wheel per- form better after βOHB addition to the diet and. including in obstetrical problems whereby the infant might be supported by βOHB during difficult labor. personal communication). its use in drug-resistant childhood epilepsy to displace the ketogenic diet awaits the availability of orally absorbable esters. pyruvate. lactate. and the ketogenic diet. A major current medical problem is the cognitive impairment of subjects undergoing cardiac surgery. It has already been used in children with congenital disorders in fat oxidation or ketone production with some dramatic success (54.

AND THE BIOMEDICAL COMMUNITY My first work in the lab of Dr. 4 Jul 2006 17:32 AR ANRV282-NU26-01. awarded me the Director’s Medal for the program’s success. I did take on one major role. I was also responsible for the NIH Cloister Program in which medical students spent one or two years at the NIH with one of the NIH staff members as his/her preceptor. budgets. which was in control of candidate selection. James Wyngaarden. (d) Mathematical Biology and Epidemiology. scientific advi- sory boards (i. and investigator reviews. the National Diabetes Commission. I was offered several chairs of medicine and deanships. A number of “experts” in the field serve on a Scientific Re- view Committee for each program. Nutr. offered me a position as an investigator. The Institute then had three programs: Endocrine-Metabolic. Cur- rently it has six programs: (a) Cell and Developmental Biology. The investigatorship covered salary and fringe benefits and eventually research support. in 1970. and Genetic. with a current total budget of about $500 million/annum. its investigators scattered at by CAPES on 04/24/08. EDUCATION. After I finished my six-year HHMI term. I joined the HHMI Scientific Advisory Board. (b) Genetics and Molecular Biology. The annual meeting for each group was an education. (e) Neuroscience and Physiology. and ( f ) Structural Biology and Biochemistry. Thorn became president in 1978. the Nutritional Advisory Board of NASA. and others. (c) Immunology and me to remain a free agent. Immunologic. No one could ask for a more exciting and educational job. Going back to 1960. I had been promoted to professor of Medicine. For personal use only. my major mentor. interrupted by clinical training and then by work on the adipose tissue.annualreviews. Harvard. Dr. Hastings. the director of the NIH at that time. who was research director of HHMI and one of its three founding officers. every gathering had one or more Nobelists either on an advisory board or as an investigator in the Institute.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 17 RESEARCH. bio-research institutes. I was promoted to associate professor of Medicine with tenure at Harvard. Rev. I was then one of Harvard’s six or eight located at the Brigham Hospital. George Thorn (7). biomedical research centers around the country. 2006. I won’t go any further except to note that I had to learn much basic sci- ence in the six disciplines. Dr. and without mentioning any names. namely with the Howard Hughes Medical Institute (HHMI). Downloaded from arjournals. chairman of Merck’s). as well as some in high schools and museums. as well as 3–5-year reviews of investigator performance.26:1-22. In 1972. HHMI was not then and is not today a foundation. brought me some recognition in the research world: I was given the Young Investigator Award of both the Endocrine Society and the American Diabetes Association.. HHMI was an institute without walls. are supported by HHMI. I subsequently became extremely busy serving with a number of governmental agencies.e. Many other activities on college campuses. and I replaced him as director of research in charge of the scientific review committees and candidate selection as well as salaries. but my disregard for administrative minutiae persuaded Annu. However. .

As its secretary/ treasurer.26:1-22. followed by Purnell Choppin. has kept me physically in reasonable shape. Lancet. The present president is Annu. I had known Lee since his research efforts at Massachusetts General Hospital. We had an apartment in Bethesda. I peruse the New York Times. we had to move to a larger auditorium. and we became reacquainted soon after my start at Dartmouth. Rev. plowing roads in winter. Anyway. Some faculty members were very much in favor and some were very opposed to this MD outsider com- peting for student attention. Some called the organization “Victor’s Hugo”! The journal Genomics is its current product. I spoke to a number of the biology faculty members and put together a proposed course on biology centered on humans and their diseases. George Thorn was made president and chairman of the board of HHMI. Within a few days. then yet again to a major facility that held more than 400 students. I also joined the MD/PhD Committee. I taught the course for seven years. My broad experience at HHMI in multiple areas of biology also led Dean Andrew Wallace to appoint me to the Board of Overseers of the school. UNDERGRADUATE TEACHING by CAPES on 04/24/08. I considered doing some teaching and met with James Friedman. New England Journal of Medicine. and our anchor was a small house built in 1834 in Stoddard. I gather. among many other activities. assisted several decades ago by our six children. At the time. one in Newton. the course was started in a classroom that held about 100 students. Donald Fredrickson subse- quently became President. However. Since Stoddard is 50 miles from Hanover. I was elevated to a vice presidency of HHMI but appreciatively resigned in 1989. and loved it. Keeping our forest trails open. Massachusetts.tex XMLPublishSM (2004/02/24) P1: IKH 18 CAHILL Other activities included the setting up of the Human Gene Organization (HUGO) with Hopkins Professor Victor McKusick as its founding president. the Institute had reviewed a grant re- quest from Dartmouth College to support their biology programs. The course continues to be taught by Professor Lee Witters and it remains a favorite. Nature. which was attended by 150 of the world’s leading human geneticists and chaired by Sir Walter Bodmer of the Imperial Cancer Institute. For personal use only. I arranged the first meeting. So. Francis Collins. Nutr. New biochemist (and Nobelist) Thomas R. The NIH soon got going and appointed James Watson to head their unit. But behind all of the aforementioned and . 2006. and mowing fields in the summer. 4 Jul 2006 17:32 AR ANRV282-NU26-01.annualreviews. The aforementioned was not good for family life. Science. then president. I was given the title of Professor of Biological Sciences. Downloaded from arjournals. and for life in general. RETIREMENT Biomedical science has been a great pleasure. The Institute funded HUGO with a $1 million grant. was a Hughes investigator at the University of Michigan. now its director. held in Building 10 at the NIH. Cech. did the students. the Economist.

Metabolic effects of glucose 9. I do not want to lose my remaining endocrine-metabolic friends! . 3:125–27 ed. Cahill GF Jr. 1915. Veech and Oliver E. Soeldner J. 26:264–82 ions and hormones on pathways of glucose. Ther. 2003. Section 7: Endocrinology. Ben. N Freinkel. J. Benedict FG. J. Richard L. Steinke J. Am. Cahill GF Jr. of Physiology. 114:149–63 neonate and infant. The role and MD. Bier Good medicine? Trans. Med. J. nol. Calzada L.tex XMLPublishSM (2004/02/24) P1: IKH FUEL METABOLISM IN STARVATION 19 continuing today is my wife and colleague of almost 56 years. Medical scientist. 10. Cahill GF Jr. Job 48 J-C. 1972. Carnegie Inst. in brief and prolonged fasted man.26:1-22. Ch. 36. 2. Aoki TT. etc. 192:491–96 3. Cahill GF Jr. Prescott P. George W. 1. Marliss EB. Cahill GF Jr. 4 Jul 2006 17:32 AR ANRV282-NU26-01. Thorn 14. our little village of Stoddard. 2005. 4. Clin. J. Senior PJ. Invest. metabolism in rat liver slices. Ahn JH. Aoki TT. Veech RL. Ashmore J. LITERATURE CITED∗ by CAPES on 04/24/08. her alma mater (Miss Porter’s School). Herrera MG. Blood glucose and the liver. Owen for reading the manuscript and making excellent suggestions. 28:507–11 Physiol. 11. Climatol. Cahill pp. handgun control. Clin. She continues to be a very busy lady and an outstanding companion. Wash. Cahill GF Jr. 1. Arcangeli MA. 45:1751–69 fasting. Hastings AB. ACKNOWLEDGMENTS My appreciation to Drs. 2001. New fast in normal children: III. 1986.annualreviews. Georges P. Pharos 68:8–15 barka MM. 77:42– 13. Diabetes Tech. Ashmore J. Effect of Am. Annu. 1966. Sally. 1973. Pediatr. Chem. 1959. Ketone body transport in the Assoc. For personal use only. J. church. 563–77 GF Jr. J. 1970. 203 12. Ashmore J. Morgan AP. Vol. Aoki TT. Nutr. Brennan MF. Muller WA. She has tolerated much and has been a major factor in both my private and professional lives. Publ. Inter. Chaussain J-L. educator. Earle AS. humanist. Cahill GF Jr. Ferré The Annual Review of Nutrition is online at http://nutr. Ketoacids? 5. et al. Downloaded from arjournals. Hormone- 224:225–35 fuel interrelationships during fasting. Cahill GF Jr. Am. Zottu S. mittent intravenous insulin therapy: a new Insulin and muscle protein. A study of prolonged Clin. 1958. Influence of Engl. DS Steiner. Dawes EA. 6-phosphate metabolism. 282:668–75 age. VIII. Med. In Handbook frontier on diabetes therapy. 1977. and to Reed Detar and Christine Maute of Computer Graphics Service at Dartmouth Medical School. Clin. Lemmel C. J. 91:711–14 7. 14 grandchildren. Bougneres PF. Renold AE. Starvation in man. Biol. 8. This is in addition to her social grace and numerous charitable activities involving hospice. J. Invest. Grecu EO. 1957.annualreviews. regulation of energy reserve polymers in ∗ I was informed that this review should be partly biographical and accordingly want to state that the references quoted are mainly those of myself and my colleagues. Studies on carbohydrate ings AB. Glycemic response to 24-hour 6. 2006. Rev. DM. Hast- Zottu S. Nutr. Glucose penetration into liver. 1975.

44 2000. models of Alzheimer’s and Parkinson’s dis- 34:761–76 ease. J. in 150 children. 24. sible role in the regulation of renal am- atic gluconeogenesis in fasting man. Renal gluconeogenesis in acidosis.annualreviews. Annu. Pillas DJ. J. The right weight: body GF Jr. monia production. Cahill GF Jr. Alanine: key role in gluconeoge. Clin. Heinbecker P. 1955. Hanson RW. 1928. Invest. J. Mongroo PB. 1970. Invest. Haymond MW. 1974. Kirsch JR. menarche and fertility. Felig P. Owen Invest. and children. Physiol. Hepatic ketogenesis and glu. Clin. alkalosis and potassium deficiency: its pos- 1969. USA 97:5440– 26. Child Neurol. J. Owen OE. D’Alecy LG. 37. women. Karl IE. Am. J. tolerance to hypoxia in the mouse. Pagliara AS. 22. Med. J. Cahill GF Jr. Clarke K. J. Butanediol induced ketosis increases hydroxybutyrate than with urine ketones. 23:986–92 longed fasting. Marliss E. 1982. Boden G. Science 167:1003–4 term fasting in men. Mori N. For personal use only. 1998. Amino acid metabolism in the reg. Marliss EB. Freeman JM. 2004. Diabetes 21:50–53 metabolism of Eskimos. 243:E251– 17. Neonatal brain injury. Marliss E.tex XMLPublishSM (2004/02/24) P1: IKH 20 CAHILL microorganisms. Biol. Proc. Physiol. J. Santiago JV. 18. Pozefsky T. Felig P. Vining EPG. Marliss E. 33. 1972. et al. Cahill GF Jr. Goodman AD. 15. Ferriero DM. Biol. J. Freeman JM. Soc. Josse RG. 1969. Protein wasting due to acidosis of pro- Clin. Takeshima T. The ketogenic diet: seizure con. Flatt JP. 7:41–46 19 16. Cahill 23. by CAPES on 04/24/08. Kashiwaya Y. Kelly MT. Cahill GF 28. Adv. Endocrinol. Veech RL. Differ- Jr. Fuisz RE. 36. ences in circulating substrates during short- longed starvation. Wahren J. ulation of gluconeogenesis in man. 29. Garrod O. Pyzik PL. Karl IE. J. Clin. 80:461–75 Pyzik BA. 1970. Menzel PH. Am. Leiter LA.26:1-22. costerone acetate on glomerular filtration Nakashima K. 1982. Goodman AD. Natl. Acad. 1980. Garber AJ. bicar- 53:113–29 bonate concentrations and pCO2 . 2005. Chem. 1994. Proc. 269:25502–14 The action of cortisone and desoxycorti. 48:584– Biochem. Hannaford MC. Physiol. Clarke WL. Mol. 27. Microbiol. 15:787–90 11:506–13 . The deposition Metabolism 31:33–42 of glycogen and water in the livers of cats. Felig P. 1967. 19. Felig P. Halperin ML. stein MB. Cahill GF Pagliara AS. Chem. Biol. Sci. S. Sato K. 1940. Haymond MW. Cahill GF Jr. strate limited disorder. Owen OE. Nutr. Fenn WO. Control of glucose 54:981–89 utilization in the perfused rat heart. 1994. Kamm DE. Downloaded from arjournals. Kashiwaya Y. Role of substrate in regulation of hep. 1974. Clin. Davies SA. Invest. Studies on the rate of ketogenesis. Pozefsky T. Chem. 4 Jul 2006 17:32 AR ANRV282-NU26-01. Biol. 25. 45:1172–77 OE. Acid-base alterations and re- fat. Steinke J. Stroke J. nal gluconeogenesis: effect of pH. Ide T. Gilbert DL. Haege LF. The efficacy of the ketogenic diet—1998: Metabolic interactions of glucose. lactate a prospective evaluation of intervention and β-hydroxybutyrate in rat brain slices. 217:784–92 63 34. Fell DA. 56 1969. Gold- Jr. 136:87–101 Ketotic hypoglycemia: an amino acid sub- 20. Adv. Rev. 10:135–266 1966. Tsuchiya S. Clin. Nutr. Invest. Pediatrics 102:1358– Am. J. Paths to discovery. Educ. Amino acid metabolism during pro. J. 33:246–51 94 30. New Engl. 31. trol correlates better with serum beta. 351:1987–95 Metab. Casey JC. 38:521–30 21. rate and sodium and water exchange in D-β-hydroxybutyrate protects neurons in the adrenalectomized dog. Nutr. J. 2000. Fuisz RE. 2006. 35. Thomas coneogenesis in humans. On the maximal possible 32. Cahill GF Jr. Clin. Frisch RE. 45:612– Enzyme Regul.

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Downloaded from arjournals. (D)-β-hydroxybutyrate in- 63. (MADD). Lardy insulin using the double antibody technic. Exp. Prostaglandins Leukot. Vari. 1972. ed. Effect of beta. Galambos JT. and mitochondrial metabolism. FASEB J. insulin Cool: Energy Flow. 2002. metabolism’s ugly duckling. Abstract 451. ketoacid excretion during starvation. Cai T-Q. Sapir DG. 1974. Strohman R. Parkin H. Diabetes 14:771–79 potential therapeutic uses. 2003. 2005. Rudman D. ketogenic diet. Williamson DH. Lancet 361:1433–35 berg R. 52:2241–49 tiple acyl-CoA-dehydrogenase deficiency 65. Van Hove JL. Sato K. on cerebral hypoxia. Annu. 2005. Neurology 64:728–30 N. Ketone bodies. Nutr. 362 pp. 2000. Aoki TT. Ruderman NB. from Myth to 64. Du. Sagan D. J. 1976. 4 Jul 2006 17:32 AR ANRV282-NU26-01. a cerebral function im. Biol. Smith RB III. Clin. 207:3149–54 24-hour fast in normal and hypoglycemic 79. Chicago Press. 1994. Rev. Fatty Acids 69. Pediatrics tions of ketone bodies: the effects of ke- 98:904–8 tone bodies in pathologic conditions: ke- 68. and ischemia in mice and rats. Transplant. 51:241–47 Nelson thesis of urea in normal and cirrhotic sub. Morgan-Boyd RL. For personal use only. Serum 81. Mehlman. Essent.26:1-22. 86:677– complex path from genotype to phenotype. 70:309–19 ables in the radioimmunoassay of serum 80. 72. Mellanby J. Into the tosis.L-3-hydroxybutyrate treatment of mul- jects. Chance B. 78. Regulation of glucose and acid receptor PUMA-G. Tsuchiya study. Kashiwaya Y. Taggart AKP. 1981. VanItallie TB. Limal JM. Di Rocco MD. 2003. proving agent. 82:90–96 . effect of carbohydrates on ammonium and Boyar NP. hydroxybutyric acid and acetoacetic acid in hydroxybutyrate. pp 515–30. Krebs HA. ischemia in the immature brain. Sato K. Chem. J. IUBMB Life 70. Macdon- chemistries in black bears in active and den. Maximal rates of excretion and syn. et al. Reality. 87:143–50 Mammalian Species. DiFulco TJ. Owen OE. Vannucci SJ. J. 2001. 1973. Hyams RD. Hypoxia- murgier E. Critical vari. Maneuvering in the hyperinsulinemic clamp. Tilney NL. Soeldner JS. ations in plasma ketone bodies during a Biol. 1962. et al. The 76. Ruderman NB. Rev. Veech RL. New York: Wiley Cheng K. 87 Science 296:701–3 82. J. 280:28849–52 Biochem. Jaeken J. 51:2093–102 diet-induced hyperketonemia: a feasibility 66. D. Thermodynamics and resistance. Ketones: bodies and mitochondrial energy transduc. 2004. 2001. Life. Schneider ED. King MT. Dihi S. Saudubray JM. Suzuki M. Keon CA.annualreviews. Gan X. 75. blood. The therapeutic implica- children: relationship to age. Kashiwaya Y. Charpentier C. Cheng JT. 2006. Simpson E. Walker WG. Nutr. Invest.5 perketonaemia in man before and during an 71. tion. Webber J. Jpn. Kero J. Declerq PE. ketone-body metabolism in rat brain. Slone D. et al. 1965. ketone 77. J. Gins. Metabolic effects of acute hy- ning sites. Grunewald S. Boden G. VanItallie TB. hibits adipocyte lipolysis via the nicotinic man J. 2003. Hagberg H. FASEB J. Treatment of Parkinson disease with Clin. HA. RW Hanson. Enzymic determination of D-(−)β- Sato T. Invest. Cahill GF Jr. Clin. Chicago: Univ. Phar- In Gluconeogenesis: Its Regulation in macol. Berger M. New York: Donnelley. Cahill GF. 2005. Biochem. 9:651–58 61:327–41 67. Heymsfield SB. Salam AA. redox states. Nonas RD. Stadtlander Lu JJ. Suzuki M. Warren WD. 320 pp. et al. Ross PS. Insulin. Marsac C. Peper RL. MA 73. J. ald IA. 2004.tex XMLPublishSM (2004/02/24) P1: IKH 22 CAHILL 62. Veech RL. Sci. anoxia Gluconeogenesis and its disorders in man. Nufert TH. by CAPES on 04/24/08. Demaerel PE. 1995. J. Good. 14(4). 138:1–10 74.

Figure 4 Overall scheme of starvation fuel metabolism. 2006. Nutr. by CAPES on 04/24/08.annualreviews. free fatty acids. Rev. For personal use only. red blood cells. muscle and kidney by complete oxidation of FFA to CO2 and H2O. Liver derives its major energy by partial oxidation of FFA to β-hydroxybutyrate and acetoacetate. HI-RES-NU26-01-Cahill. FFA.qxd 7/4/06 03:29 PM Page 1 FUEL METABOLISM IN STARVATION C-1 Annu. Downloaded from arjournals. . Brain utilizes both β- hydroxybutyrate and acetoacetate and glucose.26:1-22.

org by CAPES on 04/24/08. .qxd 7/4/06 03:29 PM Page 2 C-2 CAHILL Glucogenesis . Precursors in liver via mito- chondrial pyruvate carboxylation (white “P” in blue circle) are acetone. recycling lactate and pyruvate. it is mainly from ketogenesis. Precursors in kidney are from deamidated and deaminated glutamine with the alpha-ketoglutarate residue made into glucose via the classical mitochondrial and glucogenic intermedi- ates. 2006. Nutr. The energy (P) in kidney is derived from free fatty acids (FFA) to CO2 and H2O.Starvation LIVER KIDNEY Annu. HI-RES-NU26-01-Cahill. In liver.annualreviews.26:1-22. Rev. Downloaded from arjournals. Glycerol from adipose tissue enters the glucogenic pathway at triose phosphate. Nitrogen is returned to blood by liver urea synthesis for renal excretion and in kidney by synthesis and excretion of NH 4. For personal use only. Urea MUSCLE NH4+ Insulin Figure 5 Glucogenesis in starvation in liver and kidney. The latter titrates the renal loss of acetoacetate and β-hydroxybutyrate. and pyruvate from deaminated alanine from muscle.


Barry J. Mark D. and M. 2005 12:43 Annual Reviews AR249-FM viii CONTENTS POLYUNSATURATED FATTY ACID REGULATION OF GENES OF LIPID METABOLISM. Spruijt-Metz. PHYSIOLOGY AND BEHAVIOR.D. G.L. M. Ntambi 317 SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM: INTERACTION WITH DIETARY FACTORS. Bynum. 2006. Heird and Alexandre Lapillonne 549 INDEXES Subject Index 573 Cumulative Index of Contributing Authors. For personal use only. Allen.Q. M.annualreviews. Bradford. Goran 435 ANNUAL LIPID CYCLES IN HIBERNATORS: INTEGRATION OF by CAPES on 04/24/08. RISK AND IMPLICATIONS FOR TREATMENT AND PREVENTION BEYOND BODY WEIGHT MODIFICATION. Dolores Corella and Jose M.annualreviews. Linda Adair and Darren Dahly 407 PEDIATRIC OBESITY AND INSULIN RESISTANCE: CHRONIC DISEASE Annu. Ruden.C. Gerald M. . Harvatine 523 THE ROLE OF ESSENTIAL FATTY ACIDS IN DEVELOPMENT.P1: KUV June 15. John Dark 469 DROSOPHILA NUTRIGENOMICS CAN PROVIDE CLUES TO HUMAN GENE–NUTRIENT INTERACTIONS. Ordovas 341 THE INSULIN RESISTANCE SYNDROME: DEFINITION AND DIETARY APPROACHES TO TREATMENT. Kerry L. Volumes 21–25 608 ERRATA An online log of corrections to Annual Review of Nutrition chapters may be found at http://nutr.26:1-22. and Kevin J.J. Shaibi. Harini Sampath and James M. Ball. Volumes 21–25 605 Cumulative Index of Chapter Titles. William C. and Xiangyi Lu 499 THE COW AS A MODEL TO STUDY FOOD INTAKE REGULATION. G. Michael S. D. Douglas M. Rev. Downloaded from arjournals. Maria De Luca.I. Weigensberg. Reaven 391 DEVELOPMENTAL DETERMINANTS OF BLOOD PRESSURE IN ADULTS. Cruz.