Neuropeptide Y is a critical modulator of Leptin's regulation of cortical bone

Abstract

Leptin signaling is required for normal bone homeostasis; however, loss of leptin results in differing effects on cortical and cancellous bone, as well as altered responses between the axial and appendicular regions. Local b-adrenergic actions are responsible for the greater cancellous bone volume in leptin-deficient (ob/ob) mice; however, the mechanism responsible for the opposing reduction in cortical bone in ob/ob mice is not known. Here we show that blocking the leptin-deficient increase in neuropeptide Y (NPY) expression reverses the cortical bone loss in ob/ob mice. Mice null for both NPY and leptin (NPY -/-ob/ob), display greater cortical bone mass in both longbones and vertebra, with NPY -/-ob/ob mice exhibiting thicker and denser cortical bone, associated with greater endocortical and periosteal mineral apposition rate (MAR), compared to ob/ob animals. Importantly, these cortical changes occurred without significant increases in body weight, with NPY -/-ob/ob mice showing significantly reduced adiposity compared to ob/ob controls, most likely due to the reduced respiratory exchange ratio seen in these animals. Interestingly, cancellous bone volume was not different between NPY -/-ob/ob and ob/ob, suggesting that NPY is not influencing the adrenergic axis. Taken together, this work demonstrates the critical role of NPY signaling in the regulation of bone and energy homeostasis, and more importantly, suggests that reduced leptin levels or leptin resistance, which occurs in obesity, could potentially inhibit cortical bone formation via increased central NPY signaling. ß

High dietary fat and sucrose result in an extensive and time-dependent deterioration in health of multiple physiological systems in mice

“…Femoral BMC and BMD were measured using the DXA (Lunar PIXImus2 densitometer; GE Healthcare). The distal end of the right femur was scanned using micro-computed tomography (µCT) with a Skyscan 1172 scanner and associated analysis software (Skyscan) [50]. Femoral Images were captured at a resolution of 4.37 µm.…”

The hunger games of skeletal metabolism

“…The neurons of the arcuate nucleus have a reduced blood-brain barrier and respond to changes in circulating leptin levels to regulate the transcription of a number of genes, such as NPY. Wong et al 5 recently demonstrated that NPY was an important determinant of cortical bone mass using NPY and leptin-deficient (NPY À / À ob/ob) mice. These mice had no change in body weight but marked increases in whole-body BMD.…”

“…In addition, adipocytes secrete adipokines such as leptin and adiponectin, which respond to changes in nutritional status, obesity, inflammation and also regulate bone metabolism. [2][3][4][5] This review will outline the involvement of the gastrointestinal peptides PYY, ghrelin, GIP, GLP-1 and GLP-2, and the adipokines leptin and adiponectin, in bone homeostasis.…”

Critically Discuss the Revival of Leptin for Obesity Therapy

“…However, none of these programmes has thus far proven to be effective in achieving the long-term weight loss (Kramer et al, 1989;Wooley & Garner, 1994;Curioni & Lourenco, 2005), implying that the exact causes of obesity are still unclear. A growing number of researchers have thus turned their attention to the study on the physiological mechanisms which normally regulate food intake and body weight, in the hope of identifying the real causes of obesity and discovering effective therapies Wauman & Tavernier, 2011;Myers, et al, 2012;Panariello et al, 2012;Wong et al, 2013; It is interesting that in most adults body weight is almost constant in spite of a large variation in daily food intake and energy expenditure (St-Pierre & Tremblay, 2012). Indeed, body weight is generally maintained within a narrow range by regulating a balance between energy intake, in the form of food and drinks, and energy expenditure, in the form of basal metabolism, physical activity and adaptive thermogenesis, via the adipose-tissue-brain crosstalk (Schwartz et al, 2000;Rosen & Spiegelman, 2006;Tao et al, 2011).…”

“…These obese patients are hypothesized to develop leptin resistance that is commonly defined by the reduced capability of leptin to resist the development of obesity (Enriori et al, 2006;Morrison, 2008;Myers et al, 2008;Bjorbaek, 2009;Morris & Rui, 2009;Wong et al, 2013). Since the lack of response to leptin hinders cen- (Munzberg et al, 2005), and the type of diet (Shapiro et al, 2011), may also contribute to leptin resistance.…”