1523
J Physiol 593.7 (2015) p 1523
The Journal of Physiology
Neuroscience
PERSPECTIVES
The oestrogen–leptin paradox Geoffrey A. Head Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia Email: [email protected]
Women have lower systolic and diastolic blood pressure than men, with hypertension being less prevalent in young and middle-aged women but not in women over 60 (August & Oparil, 1999). While the cause of the rise in blood pressure in postmenopausal women is not known, the lower levels of oestrogen have been often suggested as a factor. Indeed transdermal oestrogen lowers blood pressure and sympathetic activity in postmenopausal women (Vongpatanasin et al. 2001). The adipokine leptin, a product of the ob gene, is primarily synthesized and secreted from fat as is the pancreatic hormone insulin. Both signal metabolic information to the central nervous system (CNS) via specific receptors within the hypothalamus and also signal to increase sympathetic activity and blood pressure. Oestrogen has been shown to increase the production of leptin in women and also in animal studies (Shimizu et al. 1997). While sex differences in the effects of leptin on energy balance and on interactions between leptin and oestrogen signalling have been much studied, we do not yet know whether there are sex differences in the sympatho-excitatory effects of leptin. Thus the study by Shi and Brooks in this issue of The Journal of Physiology (Shi & Brooks, 2015) is a major step forward in our understanding of the importance of oestrogen in altering the central sympatho-excitatory effects of leptin. They found that centrally administered leptin increased lumbar and renal sympathetic nerve activity (SNA) in male rats and only in females rats with high levels of oestrogen (ovariectomized plus exogenous oestrogen or during pro-oestrus). Leptin
had no effect in females rat with low levels of oestrogen (ovariectomized or during dioestrus). Not only were basal levels of renal and lumbar SNA increased, there was marked amplification of both sympathetic baroreflexes. These findings are paradoxical as males that have even lower levels of circulating oestrogen than female rats in dioestrous also show amplification of the leptin’s sympatho-excitation. Thus too little or too much oestrogen may be problematic when it comes to leptin’s actions. A major discovery by Shi and Brooks was that the sympatho-excitatory effects of leptin given centrally to rats in pro-oestrous were attenuated by 30% with a melanocortin receptor type 3/4 specific antagonist injected directly into the paraventricular nucleus. While it is not known exactly where the interaction between oestrogen and leptin occurs, it is likely to be at least partly mediated by pro-opiomelanocortin (POMC) neurons in the hypothalamus. Interestingly, oestrogen and leptin receptors co-exist on many neurons within the hypothalamus (Del Bianco-Borges et al. 2010). These results highlight the importance of understanding the interactions of oestrogen and leptin, particularly as there are marked hormonal changes at peri-menopause that may contribute to increased abdominal fat accumulation (Davis et al. 2012). Further, overweight premenopausal women with higher levels of oestrogen may be at greater risk through amplifying the sympatho-excitatory effects of leptin but whether these effects of oestrogen amplifying the sympatho-excitatory actions of leptin translate to obese subjects needs to be determined. In recent decades there has been an alarming increase in the proportion of the population that are overweight or obese in developed, as well as developing, regions. The impact on the health of the individual is profound as there is a spectrum of metabolic and cardiovascular dysfunction that is, and will continue to be, the major burden of disease in society. These include insulin resistance, dyslipidaemia,
C 2015 The Authors. The Journal of Physiology C 2015 The Physiological Society
type 2 diabetes as well as hypertension and cardiovascular disease. Thus to unravel the links between obesity and these sequelae is clearly a major health priority. However, the cardiovascular risk in men and women is not the same. Clearly further studies are also required to determine the precise site of action and to determine why females in dioestrous with lower levels of oestrogen (but higher than males) are protected from the sympatho-excitatory effects of leptin. References August P & Oparil S (1999). Hypertension in women. J Clin Endocrinol Metab 84, 1862–1866. Davis SR, Castelo-Branco C, Chedraui P, Lumsden MA, Nappi RE, Shah D & Villaseca P (2012). Understanding weight gain at menopause. Climacteric 15, 419–429. Del Bianco-Borges B, Cabral FJ & Franci CR (2010). Co-expression of leptin and oestrogen receptors in the preoptic-hypothalamic area. J Neuroendocrinol 22, 996–1003. Shi Z & Brooks VL (2015). Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of oestrogen. J Physiol 593, 1633–1647. Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N & Mori M (1997). Estrogen increases in vivo leptin production in rats and human subjects. J Endocrinol 154, 285–292. Vongpatanasin W, Tuncel M, Mansour Y, Arbique D & Victor RG (2001). Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation 103, 2903–2908.
Additional information Competing interests
There are no competing interests or conflicts of interest to declare. Funding
No funding of the work was received. G.A.H. is supported by a NHMRC Principal Research Fellowship (1002186).
DOI: 10.1113/jphysiol.2014.287763
J Physiol 593.7 (2015) p 1523
The Journal of Physiology
Neuroscience
PERSPECTIVES
The oestrogen–leptin paradox Geoffrey A. Head Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia Email: [email protected]
Women have lower systolic and diastolic blood pressure than men, with hypertension being less prevalent in young and middle-aged women but not in women over 60 (August & Oparil, 1999). While the cause of the rise in blood pressure in postmenopausal women is not known, the lower levels of oestrogen have been often suggested as a factor. Indeed transdermal oestrogen lowers blood pressure and sympathetic activity in postmenopausal women (Vongpatanasin et al. 2001). The adipokine leptin, a product of the ob gene, is primarily synthesized and secreted from fat as is the pancreatic hormone insulin. Both signal metabolic information to the central nervous system (CNS) via specific receptors within the hypothalamus and also signal to increase sympathetic activity and blood pressure. Oestrogen has been shown to increase the production of leptin in women and also in animal studies (Shimizu et al. 1997). While sex differences in the effects of leptin on energy balance and on interactions between leptin and oestrogen signalling have been much studied, we do not yet know whether there are sex differences in the sympatho-excitatory effects of leptin. Thus the study by Shi and Brooks in this issue of The Journal of Physiology (Shi & Brooks, 2015) is a major step forward in our understanding of the importance of oestrogen in altering the central sympatho-excitatory effects of leptin. They found that centrally administered leptin increased lumbar and renal sympathetic nerve activity (SNA) in male rats and only in females rats with high levels of oestrogen (ovariectomized plus exogenous oestrogen or during pro-oestrus). Leptin
had no effect in females rat with low levels of oestrogen (ovariectomized or during dioestrus). Not only were basal levels of renal and lumbar SNA increased, there was marked amplification of both sympathetic baroreflexes. These findings are paradoxical as males that have even lower levels of circulating oestrogen than female rats in dioestrous also show amplification of the leptin’s sympatho-excitation. Thus too little or too much oestrogen may be problematic when it comes to leptin’s actions. A major discovery by Shi and Brooks was that the sympatho-excitatory effects of leptin given centrally to rats in pro-oestrous were attenuated by 30% with a melanocortin receptor type 3/4 specific antagonist injected directly into the paraventricular nucleus. While it is not known exactly where the interaction between oestrogen and leptin occurs, it is likely to be at least partly mediated by pro-opiomelanocortin (POMC) neurons in the hypothalamus. Interestingly, oestrogen and leptin receptors co-exist on many neurons within the hypothalamus (Del Bianco-Borges et al. 2010). These results highlight the importance of understanding the interactions of oestrogen and leptin, particularly as there are marked hormonal changes at peri-menopause that may contribute to increased abdominal fat accumulation (Davis et al. 2012). Further, overweight premenopausal women with higher levels of oestrogen may be at greater risk through amplifying the sympatho-excitatory effects of leptin but whether these effects of oestrogen amplifying the sympatho-excitatory actions of leptin translate to obese subjects needs to be determined. In recent decades there has been an alarming increase in the proportion of the population that are overweight or obese in developed, as well as developing, regions. The impact on the health of the individual is profound as there is a spectrum of metabolic and cardiovascular dysfunction that is, and will continue to be, the major burden of disease in society. These include insulin resistance, dyslipidaemia,
C 2015 The Authors. The Journal of Physiology C 2015 The Physiological Society
type 2 diabetes as well as hypertension and cardiovascular disease. Thus to unravel the links between obesity and these sequelae is clearly a major health priority. However, the cardiovascular risk in men and women is not the same. Clearly further studies are also required to determine the precise site of action and to determine why females in dioestrous with lower levels of oestrogen (but higher than males) are protected from the sympatho-excitatory effects of leptin. References August P & Oparil S (1999). Hypertension in women. J Clin Endocrinol Metab 84, 1862–1866. Davis SR, Castelo-Branco C, Chedraui P, Lumsden MA, Nappi RE, Shah D & Villaseca P (2012). Understanding weight gain at menopause. Climacteric 15, 419–429. Del Bianco-Borges B, Cabral FJ & Franci CR (2010). Co-expression of leptin and oestrogen receptors in the preoptic-hypothalamic area. J Neuroendocrinol 22, 996–1003. Shi Z & Brooks VL (2015). Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of oestrogen. J Physiol 593, 1633–1647. Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N & Mori M (1997). Estrogen increases in vivo leptin production in rats and human subjects. J Endocrinol 154, 285–292. Vongpatanasin W, Tuncel M, Mansour Y, Arbique D & Victor RG (2001). Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation 103, 2903–2908.
Additional information Competing interests
There are no competing interests or conflicts of interest to declare. Funding
No funding of the work was received. G.A.H. is supported by a NHMRC Principal Research Fellowship (1002186).
DOI: 10.1113/jphysiol.2014.287763
