Thermogenesis, low‐protein diets, and decreased development of AFB1‐induced preneoplastic foci in rat liver

Abstract

The development of hepatocellular, putatively preneoplastic, gamma-glutamyl transpeptidase positive (GGT+) foci and tumors induced by aflatoxin B1 (AFB1) has been shown to be reduced in male F344 rats fed a diet containing 6% protein (as casein). This reduction occurs despite increased energy intake, when compared with animals fed a diet containing 22% protein. Among its many effects, low protein intake is known to increase the proportion of energy intake expended in the form of heat (thermogenesis); thus, this investigation examined the association between the development of GGT+ foci and alterations in indices of thermogenesis induced by feeding varying levels of dietary protein. Five days following the completion of AFB1 dosing, animals were assigned to groups fed 4%, 8%, 12%, 16%, or 22% dietary protein for 6 weeks. Foci development (% liver volume occupied) was markedly reduced in animals fed the low-protein diet (4%, 8%), yet calorie consumption per 100 g body wt was greater. A modest negative linear trend was observed in oxygen consumption with increasing levels of dietary protein intake. Urinary norepinephrine levels were elevated in the groups fed 4% and 8% protein; urinary dopamine and norepinephrine turnover rates in brown adipose tissue were highest in animals fed 4% protein. These results suggest that GGT+ foci development occurs when a "critical level" (approx 12%) of dietary protein intake is reached. Inhibition of foci development at lower levels of protein intake is associated with several indicators of increased thermogenesis.

Protein oxidation associated with aging is reduced by dietary restriction of protein or calories.

“…However, the 5% casein-fed rats consumed more food throughout the study period than the 20%6 casein-fed rats (about 12-15% by weight) despite the facts that the 5% casein-fed rats were smaller and the diets were isoenergetic as was seen in earlier studies (15,16,37).…”

“…26 (35). CR and PR produce alterations in various aspects of energy metabolism, including decreased body temperature (61,62) and increased physical activity with PR (54,62), but the association of CR and PR (37,61,63) or CR (62)(63)(64) with oxygen consumption is puzzling since most studies suggest that some levels of PR and CR actually increase oxygen consumption (37,61,64 The conclusions that can be drawn from this study are as follows: (i) PR inhibits oxidative damage to proteins, (ii) CR inhibits oxidative damage to proteins, (iii) PR reduces oxidative damage to proteins during the oxidative stress of chronic irradiation, and (iv) irradiation increases oxidative damage to proteins. Results of Stadtman and colleagues (7,48,49) …”

“…Both CR and PR have been shown to affect metabolic rate (10,22,36,37), but whether the restriction results in an increase or decrease of metabolic rate seems to largely depend upon the level of the restriction (37). Mild CR or PR tends to increase metabolic rate whereas severe restrictions appear to decrease the rate.…”

Stable improvement in classical B‐cell chronic lymphocytic leukemia with dietary interventions: A personal experience

“…In experiments with rats that were given the carcinogen “aflatoxin,” the link between excessive eating of animal protein (casein) and cancer was shown by two independent research teams 7,20,21 . The “critical level” of dietary protein intake was approximately 10% 21,22 . The growth of cancer tumors could be turned on and off in the same animals with a diet rich respectively poor in animal protein 23 .…”

Nutritional Renaissance and Public Health Policy

“…Because animal protein promotion of liver cancer appeared to be so substantial, convincing and provocative, the responsible mechanism was sought. Higher dietary protein (20% of calories versus 5%) 1) increased MFO enzyme activity 3- to 4-fold [ 21 – 26 ], 2) increased MFO-catalyzed activation of aflatoxin [ 21 ] to 3) a highly reactive epoxide of aflatoxin that covalently bonds to DNA [ 27 ] and produce mutations [ 28 , 29 ], 4) increased the number and/or size of pre-neoplastic cells in a dose-dependent manner (although this increase started at the recommended level of 10% protein) [ 30 , 31 ], 5) diverted dietary energy (calories) away from its normal, healthy support of voluntary exercise [ 32 ] and basal metabolism 6) through increased thermogenesis and greater brown adipose tissue activity [ 33 , 34 ] thereby favoring greater growth of cancer [ 35 , 36 ], 7) increased IGF hormone production (observed in a companion liver cancer mouse model that was initiated by hepatitis B virus and promoted by protein) [ 37 ], 8) increased production of reactive oxygen species [ 38 ] known to promote cancer [ 39 ], 9) depressed natural killer cell activity that destroys cancer cells [ 40 ] and, ultimately, 10) increased mature tumor formation and early death [ 33 , 41 – 43 ]. Also, increased dietary protein compromised DNA repair activity (unpublished).…”