Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic l... more Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is ,5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we show that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G 1 /S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a similar target critical for cell proliferation, likely MUFA, the common fatty acid product in the pathway. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, exogenous oleic acid restored the globally decreased levels of cell lipids in cells undergoing a blockade of SCD activity, indicating that active lipid synthesis is required for the fatty acid-mediated restoration of proliferation in SCD1-inhibited cells. Altogether, these observations suggest that SCD1 controls cell cycle progression and apoptosis and, consequently, the overall rate of proliferation in cancer cells through MUFA-mediated activation of lipid synthesis.
Tissue-specific effects of bovine growth hormone on lactating dairy cows were examined by analysi... more Tissue-specific effects of bovine growth hormone on lactating dairy cows were examined by analysis of milk composition. Milk samples were from 6 cows that received subcutaneous injections of 0, 5, 10, 25, 50, and 100 IU/d of growth hormone in a Latin-square design. Samples from the last 5 d of each 10-d treatment period were pooled for analyses of milk components. Concentration of alpha-lactalbumin in milk increased progressively across the treatment range up to 32% above controls (1.30 mg/nl) at the 100 IU dose. Specific alpha-lactalbumin synthesis (expressed as a percent of total milk protein) was also increased. Secretion of de novo synthesized fatty acids (short and medium chain length) in milk was increased, but response plateaued between the 50 and 100 IU/d. Secretion of preformed (long-chain) fatty acids progressively increased across the entire dose range. Thus, the percentage of long-chain fatty acids in milk increased at the highest doses of hormone. Changes in fatty acid composition of milk were apparently related to energy status; the milk response to 50 and 100 IU/d of growth hormone caused cows to be in or near negative energy balance. Exogenous growth hormone did not affect the concentration of calcium, phosphorus, sodium, iron, copper, and manganese in milk. Results are consistent with growth hormone functioning in homeorhesis to coordinate the partitioning of all nutrients to support the increased secretion of milk and milk components.
We conducted a series of experiments to evaluate the effects of conjugated linoleic acids (CLA) o... more We conducted a series of experiments to evaluate the effects of conjugated linoleic acids (CLA) on lipid metabolism and energy homeostasis in lactating dairy cows. In all experiments, multiparous Holstein cows in mid to late lactation were abomasally infused with CLA for 5 d. The initial study established that trans-10, cis-12 CLA markedly reduced milk fat yield whereas cis-9, trans-11 CLA, the predominant CLA isomer in milk fat, had no effect. Across the three investigations, infusions of the pure trans-10, cis-12 CLA isomer (3.5 to 14.0 g/d) resulted in a 25 to 50% decrease in milk fat yield and this was energetically equivalent to 6 to 11% of net energy intake. Effects were specific for milk fat as there were little or no changes in feed intake and the yield of milk or milk protein. In Exp. 1, infusing trans-10, cis-12 CLA had no effect on circulating plasma concentrations of glucose, insulin, or leptin. Basal NEFA concentrations were also unaffected, but lipolytic response to an epinephrine challenge was reduced (33%) when cows received trans-10, cis-12 CLA; this minor change in lipolytic response
Apparent absorption and retention of Ca, P, Mg, K, Cu, Mn, Zn, and S were determined in Holstein ... more Apparent absorption and retention of Ca, P, Mg, K, Cu, Mn, Zn, and S were determined in Holstein heifers treated with recombinant bovine somatotropin @ST). Six heifers (initial BW averaged 104 kg) were assigned to various doses of bST in a 6 x 6 Latin square design with six consecutive 21d periods. Treatments were daily i.m. injections of 0, 6.7, 33.3, 66.7,100, or 200 pg of WT/kg of BW on d 8 to 21 of each period. All heifers were fed a hayconcentrate diet, and nutrient digestibilities and balances were determined on d 14 to 20 of each period. Mineral concentrations in feed, water, excreta, and blood plasma were determined with an inductively coupled argon plasmaemission spectrometer. Exogenous bST did not aff& apparent absorption or retention of Ca, P, Mg, K, Cu, Mn, or Zn. Plasma CU concentration was greater (P < .05) in heifers receiving bST (82 pg of Wdl) than in those receiving excipient (73 pg of Cu/dl); plasma concentrations of other elements were not affected by bST. Injection of bST did not affect S absorption, but urinary S excretion decreased (P < .05) and S retention increased (P c .05) as dose of bST increased. The amount of S retained (1.5 g/d) when the heifers received the largest dose of bST was approximately 50% greater than the amount retained when heifers received excipient. These results demonstrate that bST affects the postabsorptive metabolism of S. Generally, bST did not affect nutrient digestibilities. Effects of bST on dietary mineral requirements were not determined because of the relatively short (14 d) treatment periods.
The utilization of energy, carbon, and nitrogen, and irreversible loss rates of nonesterified fat... more The utilization of energy, carbon, and nitrogen, and irreversible loss rates of nonesterified fatty acids were examined in lactating cows during treatment with bovine somatotropin. Six multiparous Holstein cows at approximately 62 d postpartum received daily intramuscular injections of somatotropin (29.4 mg/d) or excipient during two 21-d treatment periods in a crossover experimental design. Milk yield was increased 11% (37.1 versus 41.3 kg/d), whereas intake and digestibility of DM, energy, nitrogen, and carbon were not affected. Cows remained near zero net energy balance during both treatments (1.31 versus -1.52 Mcal/d for control and somatotropin, respectively). The major effect of somatotropin was to partition net energy into milk while tissue energy accretion was reduced. Postabsorptive use of nitrogen and carbon was altered by somatotropin as reflected by greater secretion in milk. Urinary losses of nitrogen and tissue use of carbon were reduced. Plasma concentrations and irreversible loss rates of nonesterified fatty acids did not differ between treatments. Somatotropin treatment of lactating cows results in partitioning of nutrients away from tissue deposition toward milk synthesis. The extent to which different metabolic processes are altered depends upon the energy balance of the somatotropin-treated animal.
It is rapidly becoming possible to measure hundreds or thousands of metabolites in small samples ... more It is rapidly becoming possible to measure hundreds or thousands of metabolites in small samples of biological fluids or tissues. This makes it possible to assess the metabolic component of nutritional phenotypes and will allow individualized dietary recommendations. ASNS has to take action to ensure that appropriate technologies are developed and that metabolic databases are constructed with the right inputs and organization. The relations between diet and metabolomic profiles and between those profiles and health and disease must be established. ASNS also should consider the social implications of these advances and plan for their appropriate utilization.
Bovine growth hormone (51.5 IU/day) and placebo injections were administered for 10 days to four ... more Bovine growth hormone (51.5 IU/day) and placebo injections were administered for 10 days to four Holstein cows in early lactation (wk 12) and again in late lactation (wk 35). Milk productions in the last 5 days of each period were compared. In early lactation, growth hormone increased milk yield by 15%, fat yield by 17%, protein yield by 14%, and lactose yield by 21%. In late lactation the respective increases were 31, 42, 18, and 35%. For responses of early and late lactation to growth hormone on a quantitative basis, increases for milk yield (4.3 versus 3.9 kg/day) and milk energy secretion (3.3 versus 3.4 Mcal/day) were similar. Concurrent with these increased milk yields, ad libitum intakes of a complete mixed diet declined during the period of growth hormone treatment by 3% in early lactation and 16% in late lactation. During the 6 h immediately following injections of growth hormone, blood plasma concentrations of growth hormone were elevated about 400% in early lactation and 700% in late lactation. Concentrations in plasma of free fatty acids were also higher during growth hormone treatment in late lactation but not in early lactation. Treatments did not affect plasma concentrations of glucose,
Bovine growth hormone (bGH) was administered to high-yielding Holstein cows fed a complete mixed ... more Bovine growth hormone (bGH) was administered to high-yielding Holstein cows fed a complete mixed ration ad libitum. Commencing on day 74 of lactation, 10 cows averaging 34.4 kg milk per day were divided into two groups and received a daily subcutaneous injection of bGH (51.5 IU/day) or a placebo. Injections were continued for an 11-day period and differences in lactational performance, nitrogen balance and estimated energy balance between the two groups were compared for the last 5 days of the preinjection and injection periods. Growth hormone resulted in increases of 9.5% in milk yield, 22.7% in milk fat yield, 14.5% in milk lactose yield and a 17.1% increase in milk energy secretion. Feed intake was slightly reduced (-4.3%, nonsignificant) while milk protein secretion and nitrogen balance were unchanged. Serum growth hormone levels in the bGH group were maintained at the higher concentrations of the normal physiological range during the injection period. By 48 hours following the last injection, declining bGH concentrations approached control values, and milk production decreased to preinjection values. Serum prolactin levels and plasma concentrations of free-fatty acids were slightly increased during the injection period in the bGH group. Growth hormone clearly enhances milk synthesis in the high-yielding dairy cow.
American Journal of Physiology-endocrinology and Metabolism, Apr 1, 1990
The dose dependence of plasma nonesterified fatty acids (NEFA) and glycerol responses to epinephr... more The dose dependence of plasma nonesterified fatty acids (NEFA) and glycerol responses to epinephrine was determined in lactating cows treated with bovine somatotropin (bST). Also, the effects of insulin on lipolysis and glucose clearance were examined. Lactating cows (190 +/- 24 days postpartum) received daily subcutaneous injections of methionyl bST (40 mg) or excipient during two 12-day treatment periods. Epinephrine challenges (0.1, 0.2, 0.4, 0.8, 1.2, and 1.6 micrograms/kg body wt) were administered intravenously on days 6-11 and an insulin challenge (1 microgram/kg) on day 12. Milk energy secretion increased 55% without any change in voluntary feed intake during bST treatment. Circulating concentrations of NEFA were chronically elevated and reciprocally paralleled changes in net energy balance. Maximal response of plasma NEFA and glycerol to epinephrine was markedly increased during bST treatment, whereas the dose of signal-producing half-maximal response (ED50) was unchanged. Antilipolytic effects of insulin were also enhanced, whereas the effect of insulin on the fractional rate of glucose change was reduced. Thus bST alters tissue response to homeostatic signals to allow more nutrients to be partitioned for milk synthesis. Furthermore, the alterations in response to epinephrine and insulin appear to predominantly occur at a postreceptor level.
Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic l... more Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is ,5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we show that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G 1 /S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a similar target critical for cell proliferation, likely MUFA, the common fatty acid product in the pathway. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, exogenous oleic acid restored the globally decreased levels of cell lipids in cells undergoing a blockade of SCD activity, indicating that active lipid synthesis is required for the fatty acid-mediated restoration of proliferation in SCD1-inhibited cells. Altogether, these observations suggest that SCD1 controls cell cycle progression and apoptosis and, consequently, the overall rate of proliferation in cancer cells through MUFA-mediated activation of lipid synthesis.
Tissue-specific effects of bovine growth hormone on lactating dairy cows were examined by analysi... more Tissue-specific effects of bovine growth hormone on lactating dairy cows were examined by analysis of milk composition. Milk samples were from 6 cows that received subcutaneous injections of 0, 5, 10, 25, 50, and 100 IU/d of growth hormone in a Latin-square design. Samples from the last 5 d of each 10-d treatment period were pooled for analyses of milk components. Concentration of alpha-lactalbumin in milk increased progressively across the treatment range up to 32% above controls (1.30 mg/nl) at the 100 IU dose. Specific alpha-lactalbumin synthesis (expressed as a percent of total milk protein) was also increased. Secretion of de novo synthesized fatty acids (short and medium chain length) in milk was increased, but response plateaued between the 50 and 100 IU/d. Secretion of preformed (long-chain) fatty acids progressively increased across the entire dose range. Thus, the percentage of long-chain fatty acids in milk increased at the highest doses of hormone. Changes in fatty acid composition of milk were apparently related to energy status; the milk response to 50 and 100 IU/d of growth hormone caused cows to be in or near negative energy balance. Exogenous growth hormone did not affect the concentration of calcium, phosphorus, sodium, iron, copper, and manganese in milk. Results are consistent with growth hormone functioning in homeorhesis to coordinate the partitioning of all nutrients to support the increased secretion of milk and milk components.
We conducted a series of experiments to evaluate the effects of conjugated linoleic acids (CLA) o... more We conducted a series of experiments to evaluate the effects of conjugated linoleic acids (CLA) on lipid metabolism and energy homeostasis in lactating dairy cows. In all experiments, multiparous Holstein cows in mid to late lactation were abomasally infused with CLA for 5 d. The initial study established that trans-10, cis-12 CLA markedly reduced milk fat yield whereas cis-9, trans-11 CLA, the predominant CLA isomer in milk fat, had no effect. Across the three investigations, infusions of the pure trans-10, cis-12 CLA isomer (3.5 to 14.0 g/d) resulted in a 25 to 50% decrease in milk fat yield and this was energetically equivalent to 6 to 11% of net energy intake. Effects were specific for milk fat as there were little or no changes in feed intake and the yield of milk or milk protein. In Exp. 1, infusing trans-10, cis-12 CLA had no effect on circulating plasma concentrations of glucose, insulin, or leptin. Basal NEFA concentrations were also unaffected, but lipolytic response to an epinephrine challenge was reduced (33%) when cows received trans-10, cis-12 CLA; this minor change in lipolytic response
Apparent absorption and retention of Ca, P, Mg, K, Cu, Mn, Zn, and S were determined in Holstein ... more Apparent absorption and retention of Ca, P, Mg, K, Cu, Mn, Zn, and S were determined in Holstein heifers treated with recombinant bovine somatotropin @ST). Six heifers (initial BW averaged 104 kg) were assigned to various doses of bST in a 6 x 6 Latin square design with six consecutive 21d periods. Treatments were daily i.m. injections of 0, 6.7, 33.3, 66.7,100, or 200 pg of WT/kg of BW on d 8 to 21 of each period. All heifers were fed a hayconcentrate diet, and nutrient digestibilities and balances were determined on d 14 to 20 of each period. Mineral concentrations in feed, water, excreta, and blood plasma were determined with an inductively coupled argon plasmaemission spectrometer. Exogenous bST did not aff& apparent absorption or retention of Ca, P, Mg, K, Cu, Mn, or Zn. Plasma CU concentration was greater (P < .05) in heifers receiving bST (82 pg of Wdl) than in those receiving excipient (73 pg of Cu/dl); plasma concentrations of other elements were not affected by bST. Injection of bST did not affect S absorption, but urinary S excretion decreased (P < .05) and S retention increased (P c .05) as dose of bST increased. The amount of S retained (1.5 g/d) when the heifers received the largest dose of bST was approximately 50% greater than the amount retained when heifers received excipient. These results demonstrate that bST affects the postabsorptive metabolism of S. Generally, bST did not affect nutrient digestibilities. Effects of bST on dietary mineral requirements were not determined because of the relatively short (14 d) treatment periods.
The utilization of energy, carbon, and nitrogen, and irreversible loss rates of nonesterified fat... more The utilization of energy, carbon, and nitrogen, and irreversible loss rates of nonesterified fatty acids were examined in lactating cows during treatment with bovine somatotropin. Six multiparous Holstein cows at approximately 62 d postpartum received daily intramuscular injections of somatotropin (29.4 mg/d) or excipient during two 21-d treatment periods in a crossover experimental design. Milk yield was increased 11% (37.1 versus 41.3 kg/d), whereas intake and digestibility of DM, energy, nitrogen, and carbon were not affected. Cows remained near zero net energy balance during both treatments (1.31 versus -1.52 Mcal/d for control and somatotropin, respectively). The major effect of somatotropin was to partition net energy into milk while tissue energy accretion was reduced. Postabsorptive use of nitrogen and carbon was altered by somatotropin as reflected by greater secretion in milk. Urinary losses of nitrogen and tissue use of carbon were reduced. Plasma concentrations and irreversible loss rates of nonesterified fatty acids did not differ between treatments. Somatotropin treatment of lactating cows results in partitioning of nutrients away from tissue deposition toward milk synthesis. The extent to which different metabolic processes are altered depends upon the energy balance of the somatotropin-treated animal.
It is rapidly becoming possible to measure hundreds or thousands of metabolites in small samples ... more It is rapidly becoming possible to measure hundreds or thousands of metabolites in small samples of biological fluids or tissues. This makes it possible to assess the metabolic component of nutritional phenotypes and will allow individualized dietary recommendations. ASNS has to take action to ensure that appropriate technologies are developed and that metabolic databases are constructed with the right inputs and organization. The relations between diet and metabolomic profiles and between those profiles and health and disease must be established. ASNS also should consider the social implications of these advances and plan for their appropriate utilization.
Bovine growth hormone (51.5 IU/day) and placebo injections were administered for 10 days to four ... more Bovine growth hormone (51.5 IU/day) and placebo injections were administered for 10 days to four Holstein cows in early lactation (wk 12) and again in late lactation (wk 35). Milk productions in the last 5 days of each period were compared. In early lactation, growth hormone increased milk yield by 15%, fat yield by 17%, protein yield by 14%, and lactose yield by 21%. In late lactation the respective increases were 31, 42, 18, and 35%. For responses of early and late lactation to growth hormone on a quantitative basis, increases for milk yield (4.3 versus 3.9 kg/day) and milk energy secretion (3.3 versus 3.4 Mcal/day) were similar. Concurrent with these increased milk yields, ad libitum intakes of a complete mixed diet declined during the period of growth hormone treatment by 3% in early lactation and 16% in late lactation. During the 6 h immediately following injections of growth hormone, blood plasma concentrations of growth hormone were elevated about 400% in early lactation and 700% in late lactation. Concentrations in plasma of free fatty acids were also higher during growth hormone treatment in late lactation but not in early lactation. Treatments did not affect plasma concentrations of glucose,
Bovine growth hormone (bGH) was administered to high-yielding Holstein cows fed a complete mixed ... more Bovine growth hormone (bGH) was administered to high-yielding Holstein cows fed a complete mixed ration ad libitum. Commencing on day 74 of lactation, 10 cows averaging 34.4 kg milk per day were divided into two groups and received a daily subcutaneous injection of bGH (51.5 IU/day) or a placebo. Injections were continued for an 11-day period and differences in lactational performance, nitrogen balance and estimated energy balance between the two groups were compared for the last 5 days of the preinjection and injection periods. Growth hormone resulted in increases of 9.5% in milk yield, 22.7% in milk fat yield, 14.5% in milk lactose yield and a 17.1% increase in milk energy secretion. Feed intake was slightly reduced (-4.3%, nonsignificant) while milk protein secretion and nitrogen balance were unchanged. Serum growth hormone levels in the bGH group were maintained at the higher concentrations of the normal physiological range during the injection period. By 48 hours following the last injection, declining bGH concentrations approached control values, and milk production decreased to preinjection values. Serum prolactin levels and plasma concentrations of free-fatty acids were slightly increased during the injection period in the bGH group. Growth hormone clearly enhances milk synthesis in the high-yielding dairy cow.
American Journal of Physiology-endocrinology and Metabolism, Apr 1, 1990
The dose dependence of plasma nonesterified fatty acids (NEFA) and glycerol responses to epinephr... more The dose dependence of plasma nonesterified fatty acids (NEFA) and glycerol responses to epinephrine was determined in lactating cows treated with bovine somatotropin (bST). Also, the effects of insulin on lipolysis and glucose clearance were examined. Lactating cows (190 +/- 24 days postpartum) received daily subcutaneous injections of methionyl bST (40 mg) or excipient during two 12-day treatment periods. Epinephrine challenges (0.1, 0.2, 0.4, 0.8, 1.2, and 1.6 micrograms/kg body wt) were administered intravenously on days 6-11 and an insulin challenge (1 microgram/kg) on day 12. Milk energy secretion increased 55% without any change in voluntary feed intake during bST treatment. Circulating concentrations of NEFA were chronically elevated and reciprocally paralleled changes in net energy balance. Maximal response of plasma NEFA and glycerol to epinephrine was markedly increased during bST treatment, whereas the dose of signal-producing half-maximal response (ED50) was unchanged. Antilipolytic effects of insulin were also enhanced, whereas the effect of insulin on the fractional rate of glucose change was reduced. Thus bST alters tissue response to homeostatic signals to allow more nutrients to be partitioned for milk synthesis. Furthermore, the alterations in response to epinephrine and insulin appear to predominantly occur at a postreceptor level.
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Papers by Dale Bauman