Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Abstract

Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agouti-related protein (AgRP)-expressing neurons precede proopiomelanocortin neurons in developing diet-induced cellular leptin resistance. High-fat diet-induced up-regulation of suppressor of cytokine signaling-3 (SOCS3) occurs in AgRP neurons before proopiomelanocortin and other hypothalamic neurons. SOCS3 expression in AgRP neurons increases after 2 d of high-fat feeding, but reduces after switching to a low-fat diet for 1 d. Consistently, transgenic overexpression of SOCS3 in AgRP neurons produces metabolic phenotypes resembling those observed after short-term high-fat feeding. We further show that AgRP neurons are the predominant cell type situated outside the blood-brain barrier in the mediobasal hypothalamus. AgRP neurons are more responsive to low levels of circulating leptin, but they are also more prone to development of leptin resistance in response to a small increase in blood leptin concentrations. Collectively, these results suggest that AgRP neurons are able to sense slight changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Furthermore, modulation of SOCS3 expression in AgRP neurons may play a dynamic and physiological role in metabolic fine tuning in response to short-term changes of nutritional status.M ost common forms of obesity, including diet-induced obesity, are associated with hyperleptinemia and impairment of leptin signaling in hypothalamic neurons, the hallmark feature of cellular leptin resistance. Suppressor of cytokine signaling-3 (SOCS3), a direct transcriptional product of STAT3, is up-regulated in the hypothalamus of diet-induced obese animals (1, 2). Mice with heterozygous mutation of the Socs3 gene, neuronal, or proopiomelanocortin (POMC)-specific deletion of the Socs3 gene are hypersensitive to leptin and resistant to diet-induced obesity (3-5). Conversely, up-regulation of SOCS3 in POMC neurons of chow-fed mice leads to increased body adiposity (6). In addition, wide-spread up-regulation of SOCS3 has been shown to be associated with neuronal inflammation in diet-induced obese animals (7). Thus SOCS3, which is up-regulated in chronic obesity, is commonly thought to play a pathophysiological role in obesity-associated leptin resistance.Multiple neuronal subtypes in several regions of the hypothalamus, including the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamic area, have been implicated in the regulation of energy balance and leptin action (8,9). A number of hypothalamic neurons and extrahypothalamic neurons express functional leptin receptor (10, 11). Among these neurons, POMC and agouti-related protein (AgRP) neurons are two key arcuate neuronal subtypes. POMC and AgRP neu...

Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance

“…These findings are consistent with reports that mice with targeted disruption of leptin receptor signaling in the AgRP neurons develop hyperphagia and obesity (van de Wall et al, 2008). Moreover, AgRP neurons have been reported to be one of the first hypothalamic neuronal populations to sense changes in plasma metabolic signals and develop cellular leptin resistance (Olofsson et al, 2013), possibly as a consequence of activating inflammatory signaling cascades, i.e., JNK. Indeed, it has been demonstrated that JNK activation can promote SOCS-3 expression, a well-characterized inhibitor of leptin action (Qin et al, 2007;Bjørbaek et al, 1999;Howard et al, 2004).…”

Leptin regulation of Hsp60 impacts hypothalamic insulin signaling

“…Interestingly, although acute downregulation of Hsp60 in the hypothalamus causes insulin resistance with a 2-fold increase in SOCS3 expression, these mice did not show any change in food intake or alterations in orexigenic or anorexigenic neuropeptide expression. It has been shown that a prolonged increase in SOCS3 expression in POMC and AgRP neurons causes hyperphagia (50,51), however, our data demonstrate that a short-term increase in SOCS3 expression and insulin resistance due to HSP60 dysregulation is not sufficient to alter food intake or cause obesity.…”

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

“…Nonetheless, in CAF-fed WKY rats, LepRb gene expression was downregulated by the diet, whereas Socs3 expression was slightly but not significantly decreased. This peripheral inactivation of LepRb in CAF-fed animals compared with the STD-fed ones is consistent with the over-repression of Socs3 in the hypothalamus and is supported by previous results (Olofsson et al 2013).…”

“…This strain-specific regulation of Socs3 expression by the CAF diet is highly relevant for the functionality of leptin signalling because Socs3 acts as a negative-feedback regulator of leptin signal transduction (Mori et al 2004). Thus, while the enhanced expression of Socs3 in the hypothalamus of CAF-fed LEW rats confirms the attenuation of central leptin signalling, a hallmark feature of leptin resistance (Knobelspies et al 2010, Olofsson et al 2013, the downregulation of Socs3 expression observed in CAF-fed WKY rats is associated with an increase in central leptin sensitivity. Therefore, the hyperleptinaemia in WKY rats was not translated to an attenuation of the leptin signalling, but the opposite.…”