The effects of nutrition on plasma concentrations of insulin-like growth factor-I (IGF-I) were characterized in steers under basal conditions and following single i.m. injection of bovine growth hormone (bGH, .1 mg/kg BW). Nutritional effects on IGF-I were studied in three trials. In all trials steers were individually fed and penned Angus or Hereford x Angus (280 kg). In the first trial, two diets (LPLE1: 8% CP and 1.96 Mcal ME/kg, 4.5 kg.hd-1.d-1; MPHE1: 11% CP, 2.67 Mcal ME/kg, 6.5 kg.hd-1.d-1) were fed (n = 5/diet). Plasma IGF-I concentrations averaged 74 (LPLE1) and 152 (MPHE1) ng/ml (P less than .02). Following bGH injection, IGF-I increased to peak concentrations between 12 and 24 h (averaging 105 and 208 ng/ml at peak for LPLE and MPLE, respectively, P less than .01). In the second trial, steers were fed diets composed of 8, 11 or 14% CP and 1.96 or 2.67 Mcal ME/kg dry matter (6.35 kg.hd-1.d-1 in a factorial arrangement for 84 d, n = 4/diet). Within the low ME diet groups, plasma IGF-I was similar in steers fed 11 and 14% CP but greater at these two CP levels than in steers fed 8% CP (P less than .05). Within the high ME diet groups, plasma IGF-I increased linearly with CP (P less than .01). In the third trial, steers were fed diets to result in a negative N status. Insulin-like growth factor-I was lower (P less than .02) during feed restriction than when steers were full-fed. The IGF-I response to bGH was diminished or absent in underfed steers (P less than .01). These data are interpreted to suggest that diet composition and intake affect plasma concentrations of IGF-I in steers. In cattle, CP may be the primary nutritional determinant of basal IGF-I, but the IGF-I response to CP may be affected by the available ME. Undernutrition can attenuate the IGF-I response to GH and uncouple the regulation of IGF-I normally ascribed to GH.

Beyond their nutritional effect, short-chain fatty acids, especially butyrate, modulate cell differentiation, proliferation, motility, and in particular, they induce cell cycle arrest and apoptosis. A bovine kidney epithelial cell line (Madin-Darby bovine kidney; MDBK) was used to investigate the cell cycle regulatory and apoptotic effects of butyrate. Butyrate not only induced apoptosis but also induced cell cycle arrest at the G1/S boundary and M/G2 in MDBK cells (P < 0.01). The cell responses were concentration-dependent (r(2) = 0.9482, P <0.001). In examining possible mechanisms for the apoptosis and cell cycle arrest induced by butyrate, the results showed that butyrate treatment activates caspase-3 activities and induces accumulation of acetylated histone. At least two proteins, cdc6 and cdk1, become targeted for destruction on butyrate treatment. These two proteins are downregulated (P < 0.01 and P < 0.05, respectively) by proteolytic pathways. Moreover, the proteasome inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) reverses the cell cycle arrest induced by butyrate, indicating a multiprotein crosstalk wherein the ubiquitination/ proteasome pathway interacted with the caspase-signaling pathway. Because the proteasome inhibitor MG-132 blocked activation of caspase-3, these results functionally locate the proteasome pathway upstream of the caspase pathway. All these results indicate that butyrate functions as both a nutrient and signaling molecule regulating cell growth and proliferation.

Endotoxin, a potent stimulator of the immune system and an important mediator in the pathophysiology of septic shock, has been shown to alter the release of certain hormones following its systemic administration. The purpose of this study was to determine the effects of endotoxin on pituitary hormone secretion both in vivo and in vitro in sheep, with emphasis placed on its effects on growth hormone (GH) release. Endotoxin (400 ng/kg i.v.) increased plasma GH, adrenocorticotropic hormone (ACTH), cortisol and prolactin, while it decreased luteinizing hormone (LH) pulse frequency (p < 0.05). Plasma levels of tumor necrosis factor, a major mediator of endotoxin effects, also increased following endotoxin administration. Endotoxin did not affect the GH response to human GH-releasing hormone. In vitro studies evaluated the effect of endotoxin to alter GH secretion from dispersed sheep anterior pituitary cells at dosages of 1, 10 and 50 µg/ml, with samples collected at 4, 8 and 24 h. Endotoxin increased pituitary GH secretion at 24 h for 1 µg/ml (p < 0.05) and at all time periods for 10 and 50 µg/ml (p < 0.05). It also led to an increased release of ACTH and LH in vitro. The results of this study demonstrate the ability of endotoxin to alter pituitary hormone secretion both in vivo and in vitro in sheep, suggesting a direct effect of endotoxin on the pituitary gland.

The upregulation of adrenomedullin (AM) gene expression and increases in systemic circulatory as well as localized tissue AM concentrations is well coordinated with the onset and progression of trauma, infection, and sepsis. As such, the coordinated change in AM suggests a key role for this peptide in the inflammatory response. By clinical definition, the process of inflammation constitutes an orchestrated cascade of localized tissue and systemic responses to immunological challenges. Classical responses to the onset of disease stresses are manifested in the timely elaboration of humoral, blood-borne signal effectors (such as adrenocortical and locally produced tissue hormones, immune cytokines, and inorganic signals such as nitric oxide) as well as patterned migration and infiltration of circulating bone marrow-derived cells (mononuclear cells such as monocyte-macrophages and polymorphonuclear cells like neutrophils) largely associated with or delivered through the vascular system. The body's attempts to combat acute infection to restore homeostatic equilibrium are further compromised by underlying disease situations. Atherosclerosis, diabetes, and cardiovascular disease, as well as nutritional metabolic derangements and persistent subclinical infection perturb the regulatory feedback loops necessary for proper control of response effectors like hormones and cytokines. When imbalances occur, tissue necrosis can ensue as driven by free radical damage to cell components. A true appreciation of the inflammatory response can only be grasped through an integrative approach in which the relationship between the different physiological systems is viewed in terms of a changing, dynamic interaction. In essence, the inflammatory response can be thought of in three phases: a period of severity assessment, a period of remediation, and a period of homeostatic restoration. Indeed, AM has differential effects on cellular metabolism, immune function, endocrine function, and cardiovascular function. This peptide appears to play a pivotal role in both reprioritizing the biological needs of tissues and organs during the three phases of inflammatory response as well as a role in restoring homeostatic equilibrium to the body.