Fat and Sexy

Fat and Sexy: The role of Leptin in puberty Erin Slaten Special Topic Psychology 235 2/28/07 Overview Puberty The neuroendocrine timing of puberty Leptin How does Leptin relate to puberty? What is Puberty  Puberty = attainment of fertility  Morphological, physiological, and behavioral development  Increase hypothalamic secretion of gonadotrophin-releasing hormone decapeptide (GnRH) is essential for the activation of the pituitary-gonadal axis at puberty.  Puberty is the reactivation of GnRH secretion. Reactivation of GnRH secretion GnRH secretory system initially active in mid-late fetal or neonatal period. Early activation needed for brain masculinisation. GnRH secretion actively inhibited or dormant during prepubertal period Puberty = reactivation of GnRH secretion Independent of gonadal steroid feedback What triggers puberty onset? Mechanism triggers reactivation of GnRH neurons? Hypothalamic GnRH neurons produce GnRH GnRH stimulates the anterior pituitary to produce FSH and LH FSH & LH act on the gonads in males and females and triggers the onset of puberty. Timing of puberty is a function of changes in the neural systems controlling GnRH. The Neuroendocrine Timing of Puberty Age & Weight in Puberty Onset •Age of menarche onset in USA = under 13 •Other Western European countries = 13-15 •Critical weight = 45kg or approx. 100lbs •25% adolescents in USA overweight in 1994 •15% overweight in 1980 •Timing is not simply a function of chronological age. •Puberty is more dependent on size than age. Body fat and puberty  Body weight hypothesis: Correlation between early onset of puberty and weight/body fat gain points to a mechanistic link between energy metabolism and the GnRH secretory system.  Caloric availability is the key element determining reproductive function.  Fat is a correlate of positive energy balance rather than the causal factor in puberty onset. What is Leptin?  Derived from Greek word “leptos” (thin)  Protein hormone (cytokine)  167 amino acids  Secreted in fat  Acts on the CNS through leptin receptor (ob-Rs)  Suppression of food intake and increase energy consumption Leptin acts on various tissues •Leptin receptors identified in the hypothalamus, pancreas, ovaries, testes, uterus, kidneys, heart, lung, liver, skeletal muscles. • Main action of leptin is in hypothalamus where it reduces the secretion of NPY and food intake Where are leptin receptors (Ob-R) found in the brain? Female monkey hypothalamus: •Ventral Medial Nucleus (VMN) •Arc •Median Eminence (ME) •Lateral Hypothalamus Secretion of Leptin  24 hour cycle: Higher rates during the evening Lower rates in the morning  Night increase due to accumulating hyperinsulinemia (too much insulin in the blood) during the day.  Normal cycling women: Leptin peak in mid-secretory phase Coincides with an increase in progesterone secretion. Pulsatile release pattern assoc. with variations in LH and estradiol levels. Sexual Dimorphism •Leptin levels in girls increase with age •Leptin levels in boys rise before puberty and then fall off. •Trend continues into adulthood: leptin levels higher in women than men. •Androgens reduce secretion of leptin. •Higher testosterone in men causes reduction in leptin levels. Metabolic cues to the onset of puberty Leptin works here as an internal metabolic cue Leptin: Action on GnRH secretory network •Leptin does not act directly on GnRH neurons (no leptin receptors on GnRH neurons) •Leptin can directly stimulate GnRH secretion (through other neuropeptides). How do metabolic cues interact to time puberty? •Ultimately still an unknown mechanism •Leptin not responsible for direct onset of puberty, however does play “permissive” role in the timing of puberty. •If enough leptin (body fat) is around then puberty will occur. Leptin deficient ob/ob mice Widtype Ob/Ob  Mice with mutated leptin gene or receptor and hormone insufficiency  Both male and female obese and infertile  Weight loss did not lead to reinstatement of fertility  Administration of leptin reinstates fertility  Normal mice given leptin  early puberty onset Primate Animal Experiment •Two male monkeys fasted for two days •Each animal received both treatments of leptin and saline on separate occasions. •Monkey who received leptin showed LH pulsatility. •Monkey who received saline showed suppression of LH pulses. Either leptin regulates LH release or another factor regulates both leptin & LH release in a synchronous manner (no leptin = lack of LH pulses) Leptin Dysfunction •9 yr. old girl with a nonfunctional leptin gene •Treatment with leptin reinstates pulsatile secretion of FSH an LH. •Looks like early puberty •Women with menstruation disorders initially present with a disruption of their 24-hr leptin secretion cycle. •Anorexic women have very low leptin levels. •However, two women identified with leptin deficiency and have normal reproductive function. Take away leptin = no menstruation! Conclusion  GnRH secretory network receives info about metabolic fuels, energy stores, somatic development, season and social environment and triggers puberty.  Leptin is secreted by fat and acts indirectly (through other neuropeptides) on the GnRH neurons of the hypothalamus.  Take away leptin no menstruation.  Not enough leptin delay of puberty or puberty will not be attained.  Leptin is a metabolic signal to the neuroendocrine reproductive system and that under conditions of inadequate energy reserves, low leptin levels act as a metabolic “gate” to inhibit the activity of the neuroendocrine reproductive axis in both sexes.  Leptin is a link between energy reserves and neural networks controlling reproduction.