Gestational Low-Protein diet Programming on Sex Steroid Hormone Synthesis

Offspring born to mothers with nutritional stress during pregnancy have increased susceptibility to metabolic diseases including diabetes and hypertension during their adult life. Low protein (LP) diet during pregnancy in rats has been shown to cause lean Type 2 Diabetes (T2D) in adult offspring. In addition, testosterone in males and estradiol in females were also reduced in these animals. The pathophysiology of lean T2D and its associated reductions in sex steroid hormone synthesis are poorly understood, and the mechanistic insights are critical for the development of therapeutics. Therefore we will use this LP diet programmed lean T2D rat model we recently developed, to investigate the mechanisms for the reduced sex steroid hormone synthesis in males. Changes in metabolic functions of skeletal muscle and liver, and in sex steroid synthesis in gonads in this model appears to be related to mitochondrial dysfunctions. In recent studies, we found ultrastructural deformities with loss of cristae and appearance of giant mitochondria as well as changes in key genes involved in various vital mitochondrial structure and function in metabolic these tissues. Impaired quality control often results in suboptimal mitochondrial function, which affects steroidogenesis. Steroidogenesis is also regulated by characteristics of the mitochondrial interaction with the endoplasmic reticulum (ER). Mitochondrial quality and ER tethering are interdependent because the ER assists the mitochondria in fission and mitophagy. The role of the intracellular cholesterol pool and its dynamics in sex steroid synthesis are also not well understood. Pilot data from our lean T2D model suggests that mitochondrial-ER membrane contacts are reduced, and intracellular cholesterol trafficking is altered in the gonads of LP-programmed T2D animals. We hypothesize that LP diet during pregnancy causes impairment of mitochondrial quality, ER-mitochondrial association, and cholesterol homeostasis in Leydig cells of male offspring leading to lower testosterone synthesis Two specific aims are proposed. Aim 1: Determine if LP diet during pregnancy causes reductions in mitochondrial-ER membrane contacts and mitochondrial quality in Leydig cells of male offspring. Aim 2: Assess if LP diet during pregnancy impairs mitochondrial metabolism and intracellular cholesterol regulation in Leydig cells of male offspring. The studies proposed are significant because we will be the first to investigate mechanisms into the mitochondrial dysfunction associated with reduced sex steroid production in LP programmed offspring.