Tyrosine Hydroxylase Activity in Sympathetic Nervous System of Rats With Streptozocin-Induced Diabetes

Abstract

The activity of tyrosine hydroxylase (TOH), the rate-limiting enzyme in norepinephrine biosynthesis, was measured in selected sympathetic ganglia to develop a quantitative measure of sympathetic autonomic neuropathy in streptozocin-induced diabetic rats. Surprisingly, TOH activity was elevated twofold in diabetic prevertebral ganglia innervating the alimentary tract (i.e., superior mesenteric, celiac, and inferior mesenteric), which has terminal processes that develop neuroaxonal dystrophy in this model system. TOH activity of paravertebral ganglia (i.e., superior cervical and stellate) with nonalimentary targets was not increased in the same animals. Increased TOH activity in the prevertebral ganglia 1) developed within the 1st wk of diabetes and persisted for 10 mo, 2) did not represent a change in TOH affinity for d-1,6-methyl-5,6,7,8- tetrahydropterine cofactor, 3) was prevented by both nicotinamide pretreatment and early institution of insulin therapy, and 4) did not develop as a result of classical transsynaptic induction. Pair-feeding experiments confirmed that the most likely cause of increased TOH activity in this system was the marked hypertrophy and hyperplasia of the diabetic bowel resulting from compensatory hyperphagia. We conclude that TOH activity does not represent a suitable marker for sympathetic autonomic neuropathy in this experimental system. Rather, the increase appears to be an example of a selective increase in the synthesis of neurotransmitter enzymes, possibly in response to increased trophic support provided by the expanded target, i.e., the hypertrophic gut. The additional synthetic stress imposed on prevertebral neurons by the expansion of the innervation of the alimentary target coupled with the complex diabetic metabolic milieu may contribute to the development and selective distribution of dystrophic axonopathy to the innervation of the alimentary tract.

Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit

“…Consequently, butyrate activates BAT and increases oxidation of intracellular fatty acids resulting in a compensatory influx of TG-derived fatty acids. In fact, butyrate increased in BAT the protein level of TH, which is a marker of SNS activity 39. In vagotomised mice, butyrate failed to increase the uptake of TG-derived fatty acids by BAT, the utilisation of lipid in BAT as well as the protein level of UCP-1, a positive marker for BAT activation.…”

Vascular-dependent effects of elevated glucose on postganglionic sympathetic neurons

“…This indicates that in these patients, NE released by functioning postganglionic neurons, including vascular neurons, affects blood pressure and blood flow. Morphological analyses in humans and rats indicate that some, but not all, postganglionic sympathetic neurons are susceptible to hyperglycemia (30,31,33,34). Vascular sympathetic neurons were not specifically identified in these studies, but additional evidence indicates that the function of this subset of postganglionic sympathetic neurons is maintained in hyperglycemic animals.…”

“…STZ was used to induce hyperglycemia in adult male rats. This model is routinely used as a model of hyperglycemia and type 1 diabetes (2,9,20,25,30,35). Western analyses indicate that 7 days of hyperglycemia did not affect TH or GAP43 expression in cell bodies of postganglionic sympathetic neurons in superior cervical ganglia (Fig.…”

Autonomic neuropathy in experimental models of diabetes mellitus

“…Subsequently, decreased endogenous NGF in the SCG of STZ-diabetic rat was reported in the presence of increased or unchanged NGF content in iris, heart, and spleen (Hellweg and Hartung, 1990). However, the diabetic rat SMG develops ND but does not lose neurons (Schmidt, 2001), show perikaryal atrophy (Schmidt and Plurad, 1986) or decrease TOH and DbH activities (Schmidt and Cogswell, 1989), as would be expected in a true substantial NGF deficiency. Autoimmune NGF depletion does not produce ND in nondiabetic rat SMG (Schroer et al, 1995).…”