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Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from [G.sub.i/o] GPCRs by G[beta][gamma] subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of G[beta][gamma] with soluble N- ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25A3) that decreased G[beta][gamma] affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-G[beta][gamma] inhibition of SNARE- mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. Snap2SA3/A3 mice exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap2SA3/A3 mice challenged with a high-fat diet. Glucose homeostasis, whole-body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. Metabolic protection in [Snap25.sup.[DELTA]3/[DELTA]3] mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting that basal autonomic activity was required. Direct electrode stimulation of sympathetic neuron exocytosis from [Snap25.sup.[DELTA]3/[DELTA]3] inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the G[beta][gamma]-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combating metabolic disease., Introduction Metabolic diseases, such as diabetes and obesity, have an estimated annual global economic impact in the trillions of (US) dollars (1-5). Therapeutic approaches to lower metabolic risk include augmenting [...]

A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through β-adrenergic receptor (βARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor or pharmacologic rapamycin treatment, were refractory to the well-known βAR-dependent increase of uncoupling protein UCP1 expression and expansion of beige/brite adipocytes (so-called browning) in white adipose tissue (WAT). Mechanistically, PKA directly phosphorylated mTOR and RAPTOR on unique serine residues, an effect that was independent of insulin/AKT signaling. Abrogation of the PKA site within RAPTOR disrupted βAR/mTORC1 activation of S6K1 without affecting mTORC1 activation by insulin. Conversely, a phosphomimetic RAPTOR augmented S6K1 activity. Together, these studies reveal a signaling pathway from βARs and PKA through mTORC1 that is required for adipose browning by catecholamines and provides potential therapeutic strategies to enhance energy expenditure and combat metabolic disease., Introduction Adipose tissue depots in both humans and rodents perform a remarkable spectrum of contrasting functions, including sequestration of excess caloric energy in the form of triglyceride in white adipose [...]