Regulation of inflammatory signalling in adipocytes by AMPK

AMP-activated protein kinase (AMPK) has been proposed to be a potential therapeutic target for patients with Type 2 diabetes and the metabolic syndrome. While the role of AMPK in muscle and liver is relatively well-characterised, less is known about the role of AMPK in the other principal metabolic tissue, adipose. Obesity is associated with the chronic, sub-clinical inflammation of adipose tissue. Characteristic hypertrophic adipocytes and the elevated infiltration and activation of macrophages stimulate production of cytokines and chemokines, including tumour necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). These have autocrine, paracrine and endocrine effects which have been suggested to play a key role in the development of peripheral insulin resistance. Increasing evidence suggests that AMPK has anti-inflammatory actions, independent of its effect on carbohydrate and lipid metabolism. Previous work in our laboratory has demonstrated that AMPK inhibits TNF-alpha-stimulated MCP-1 secretion and monocyte adhesion in endothelial cells. The role of AMPK in the regulation of inflammatory signalling in adipocytes is currently poorly characterised. To address this, the effect of AMPK activation on the phosphorylation of TNF-alpha/IL-1beta and IL-6 signalling pathway intermediates was initially assessed in cultured 3T3-L1 adipocytes. Furthermore, the molecular mechanism by which AMPK elicits these effects was investigated. In addition, the effect of AMPK activation on downstream functional consequences of proinflammatory signalling in 3T3-L1 adipocytes and RAW 264.7 macrophages were examined. Finally, the effect of macrophage AMPK activation on inflammation-induced insulin resistance in 3T3-L1 adipocytes was also investigated. A769662 and infection with adenovirus expressing a constitutively active AMPK mutant suppressed IL-1beta-stimulated NFkappaB nuclear translocation in 3T3-L1 adipocytes. Conversely, this was abrogated upon adenoviral expression of a dominant negative AMPK mutant. In line with this, phosphorylation of upstream IkappaBalpha and IKK were also ameliorated upon AMPK activation. In parallel, A769662-mediated AMPK activation inhibited TNF-alpha/IL-1beta-stimulated phosphorylation of JNK, ERK1/2 and p38 MAPKs in 3T3-L1 adipocytes. Furthermore, A769662-mediated inhibition of TNF-alpha/IL-1beta proinflammatory signalling was likely to be independent of endothelial nitric oxide synthase (eNOS) activation and subsequent nitric oxide production. The target of AMPK may be downstream of TAK1, as IKK, JNK and p38 are inhibited in response to both TNF-alpha and IL-1beta; however the mechanism by which AMPK elicits these effects remains to be elucidated. A769662-mediated AMPK activation inhibited phosphorylation of IL-6-stimulated STAT3 (signal transducer and activator of transcription 3) in 3T3-L1 adipocytes independently of phosphatase action, yet A769662 was unable to inhibit constitutive Janus kinase (JAK)-mediated phosphorylation of STAT3, suggesting AMPK may inhibit JAK activity. Inhibition of mTOR was found to suppress STAT3 phosphorylation in a manner mutually exclusive with A769662 stimulation, potentially via activation of T cell protein tyrosine phosphatase (TC-PTP). Adipose tissue from AMPKalpha1-/- mice demonstrated increased basal JNK and STAT3 phosphorylation, further providing evidence for an anti-inflammatory role for AMPK in adipose tissue. In 3T3-L1 adipocytes, A769662 abrogated cytokine-stimulated MCP-1 gene expression, and secretion of chemokines IP-10 (CXCL10), KC (CXCL1) and MCP-1. Furthermore, AMPK activation reduced secretion of IL-5, MCP-1 and MIP-1alpha, but not TNF-alpha, from proinflammatory RAW 264.7 macrophages. Preliminary results indicated that chronic IL-6 and acute TNF-alpha or IL-1beta exposure suppressed insulin-stimulated glucose transport in 3T3-L1 adipocytes. Conditioned medium from activated RAW 264.7 macrophages also inhibited 3T3-L1 adipocyte insulin sensitivity; however, prior AMPK activation failed to attenuate this, potentially as a result of the presence of TNF-alpha. Overall these results suggest that activation of AMPK inhibits activation of multiple distinct proinflammatory signalling pathways in adipocytes and macrophages. AMPK activation may suppress IL-6 signalling via regulation of JAK, while the AMPK-mediated inhibition of IKK and concomitant suppression of MAPKs in response to TNF-alpha/IL-1beta suggests TAK1 as a potential AMPK target. Finally, proinflammatory stimuli induce insulin resistance in adipocytes, however whether this can be rescued by AMPK activation remains to be fully elucidated

Consumer Fraud, Home Financing, and the Erosion of Trust

Consumer fraud is a civil violation of a remedial statute not requiring specific intent to deceive. Most consumer fraud statutes define violations as unconscionable, misleading, or deceptive practices irrespective of intent, in derogation of the principle of caveat emptor. They do not apply to business-to-business transactions. Trust plays a central role in business-to-consumer transactions. Because consumers are individuals, there is often an inherent inequality in consumer transactions. Sophisticated marketing techniques—especially target marketing that follows potential customers all over the internet—hound consumers’ online lives and manipulate purchasing decisions. The increasing monetization of almost everything exacerbates these effects. This transactionalism itself erodes trust because commercial trust is less robust than interpersonal trust. “Consumers” are not a monolithic category and the effects of consumer fraud depend on one’s education, business sophistication, and ethnicity. The neoclassical model of a universal, rational, self-interested, decontextualized individual has numerous limitations, and we now know that rationality is bounded in any event—we are unable to incorporate all relevant information in our decision-making. Further, the neoclassical model does not accurately represent the financial situations and daily realities of most American consumers, who are working to middle class, struggling economically, and lacking in financial literacy. This Essay applies this framework to the phenomenon of home lending fraud, which was the primary cause of the Great Recession and the worldwide financial meltdown of 2008. Home lending fraud of all sorts erodes trust in our system and country. Trust tends to be eroded more in consumers who do not realize the risks taken when entering into these transactions, which is disproportionally the case with lower income consumers. They are hit especially hard because they have fewer resources, and if they own a home, it is generally their only valuable asset. In this Essay, I focus particularly on the example of land contracts—rent-to-own arrangements often accompanied by predatory features—that have looted many millions of dollars of wealth from low- to moderate-income Americans. The Essay finally turns to the post-Great Recession Dodd–Frank Act and its creation of the Consumer Financial Protection Bureau. The Bureau is the first federal agency with the sole mission to regulate consumer financial products. Dodd–Frank regulations and oversight have helped increase trust in consumer financial markets since the last financial crisis. Supervision of lending institutions—some of which were not previously subject to federal regulation—is a critical tool in resisting forces that continue to undermine trust in our system

Unmet Promises: Reverse Mortgage Servicing Challenges and How to Preserve Housing Stability for Older Adults

There are roughly 480,000 reverse mortgages currently outstanding in the United States. This number is expected to grow as baby boomers age. The program was designed to allow older homeowners to borrow against their home equity without the risk of displacement, but reverse mortgages end in foreclosure much more often than they should. Reverse mortgage borrowers who fall behind on property charges face significant hurdles to obtaining a narrow set of home retention options. Heirs struggle to access information necessary to satisfy the reverse mortgage without the need for foreclosure. Spouses who are not listed on loan documents, often termed "non-borrowing spouses," can generally remain in the home if they keep paying the property taxes, but are not eligible for loss mitigation. Servicers too often foreclose based on supposed non-occupancy when the borrower is still occupying the home. Across all of these situations, poor servicing communication and insufficient access to housing counseling exacerbate the problems.Resolving these problems is particularly important because of the effect of preventable reverse mortgage foreclosures on the racial wealth and homeownership gap. The crisis of preventable reverse mortgage foreclosures does not impact all communities equally. Historically, people of color have been more likely to take out reverse mortgages, due to the legacy of discrimination and policies that limited their wealth-building opportunities, and they are also more likely to end up in reverse mortgage foreclosure. The heirs of reverse mortgage borrowers of color may lose significant home equity if they are not able to sell or refinance the home to satisfy the loan. When it comes to addressing the racial wealth gap and racial homeownership gap, reducing the number of preventable reverse mortgage foreclosures is an important and necessary step.The FHA reverse mortgage program has not lived up to its full potential. Based on the information uncovered in this report, we call on FHA and the Consumer Financial Protection Bureau (CFPB) to act quickly to prevent any additional home losses for this vulnerable population

Health-Related Quality of Life Outcomes With Tofacitinib Treatment in Patients With Ulcerative Colitis in the Open-Label Extension Study, OCTAVE Open

BACKGROUND Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We report health-related quality of life (HRQoL) outcomes in patients with ulcerative colitis in the phase 3 open-label, long-term extension study, OCTAVE Open. METHODS The Inflammatory Bowel Disease Questionnaire (IBDQ), EuroQoL-5 Dimensions Health Questionnaire, and 36-Item Short Form Survey scores were analyzed up to month (M) 72 in 4 subpopulations: patients in remission at baseline (maintenance remitters) assigned tofacitinib 5 mg twice daily and patients not in remission at baseline (maintenance nonremitters, maintenance treatment failures, and induction nonresponders [IndNRs]) assigned tofacitinib 10 mg twice daily in OCTAVE Open. Data were analyzed overall and stratified by corticosteroid use at baseline, prior tumor necrosis factor inhibitor failure, and prior immunosuppressant failure. RESULTS Among maintenance remitters and nonremitters, HRQoL outcomes were maintained up to M72: 80.0% and 100.0% of patients had an IBDQ total score ≥170, respectively. At baseline, 7.4% of maintenance treatment failures had an IBDQ total score ≥170, and this increased to 54.3% and 75.0% at M2 and M72, respectively. Corresponding values for IndNRs were 22.6%, 51.0%, and 86.0%. HRQoL outcomes were independent of treatment history. Among patients not in remission at baseline, improvement in EuroQoL-5 Dimensions Health Questionnaire and 36-Item Short Form Survey scores was maintained or achieved by M2, and steady to M72 or M33, with maintenance treatment failures and IndNR subpopulations undergoing the biggest improvements from baseline. CONCLUSIONS A continued favorable impact on HRQoL was revealed with long-term tofacitinib treatment in OCTAVE Open, regardless of baseline remission status or treatment history. (ClinicalTrials.gov; number: NCT01470612)

“What Shall I Give My Children?”: Installment Land Contracts, Homeownership, and the Unexamined Costs of the American Dream

Gwendolyn Brooks’s “The Children of the Poor is a meditation on parenthood in times of hardship, with a particular focus on the impact of poverty and social injustice. The title of this Comment comes from the second sonnet of Brooks’s tripartite poem: “What shall I give my children? who are poor,/ Who are adjudged the leastwise of the land.” In the poem, Brooks asks an immediate question: How will she respond to her children’s requests right now for material goods and acceptance that she cannot give them? Unable to fulfill those needs, the mother in the poem instructs her children in their reality, providing lessons that will hopefully support them throughout their lives. This is the much larger question for parents, who worry not just for their children’s present but also for their future. Echoing Brooks’s simultaneous focus on material needs and emotional resilience, this Comment is about home ownership—the cornerstone of the American Dream and an “essential” for anyone hoping to pass on generational wealth to their children. Historically, there can be no doubt that home ownership has allowed a great many Americans, primarily White Americans, to build wealth and provide their children with financial stability. For those Americans able to become homeowners, especially those who did so in the mid-twentieth century, the promises of home ownership have been fulfilled. But for those cut out of the primary home ownership market, especially Black Americans, those promises have largely proved empty. In fact, the financing devices available to low-income and minority communities have had significant adverse effects on those communities and their ability to pass on any kind of wealth or prosperity to their children. This Comment explores the installment land contract (ILC), one financing device that has been used in lieu of a mortgage for those who cannot qualify for traditional mortgage financing. The ILC was especially prominent during the mid-twentieth century in Black communities shut out of the mortgage market by the Federal Housing Administration. Since 2008, the ILC has again become popular: increased regulation of the mortgage market has made it more difficult for low-income home buyers to get mortgages, but the underlying desire to participate in the American Dream has not changed. This Comment looks at the history of the ILC and,using that as a backdrop, explores the best way to take advantage of the financing device while still protecting potential buyers from the worst of its associated risks. To that end, this Comment concludes that current regulation is inadequate to appropriately deal with the risks of the ILC. This Comment proposes the adoption of three protective measures: (1) imposing mandatory purchase counseling,(2) creating venue requirements that prohibit eviction courts from hearing ILC cases, and (3) making per se unconscionable all ILCs that include both an “as is” deed and a forfeiture clause

The Current Predatory Nature of Land Contracts and How to Implement Reforms

Because land contracts are frequently inequitable, advocates and legislators have called for enhanced regulation. This Note examines the imbalance of power between sellers and buyers during the formation of land contracts, the ways the law has attempted to lessen the inequality, and how to implement potential reforms. Part II discusses the history of land contracts and their recent resurgence since the 2008 housing crash. Part III explains that while current land contracts are often predatory, land contracts could potentially be a useful way for low-income individuals to become homeowners. Part IV outlines proposed national and state reforms. Part V makes recommendations for future reform and discusses potential obstacles to the implementation of two of the most promising reforms: mandatory independent inspections and mandatory independent appraisals

Me, Myself and My Digital Double: Extending Sara Greene’s Stealing (Identity) from the Poor to the Challenges of Identity Verification

Identity is an essential part of the human condition. When one’s identity is stolen or when a state rejects a citizen’s identity, the consequences can be devastating to one’s notion of selfhood as well as undermine their economic security. In Stealing (Identity) from the Poor, Sara Greene explores the serious harms suffered by low-income people who are victimized by identity theft. She explains that our plutocratic regime of identity theft laws serves the interests of wealthier Americans at the expense of those experiencing poverty. This Essay extends Greene’s analysis and framing to the harms of identity verification systems, particularly in unemployment insurance (UI) programs. During the COVID-19 pandemic, UI programs faced massive demands as people lost work, and criminal syndicates fraudulently claimed billions of dollars in benefits. In response, states hastily adopted automated identity verification systems that ended up denying benefits to millions of needy and eligible workers. These systems failed along three dimensions. First, they were designed with privileged users in mind, thus leaving vulnerable people in the digital divide unable to navigate their requirements. Second, identity verification determinations were implemented without adequate due process or clear standards. Third, the privatization of identity verification systems limited transparency and accountability to citizens. This Essay explores the challenges of identity verification in our automated age and suggests several paths forward for more equitable systems

The High Cost of Eviction: Struggling to Contain a Growing Social Problem

Matthew Desmond’s Pulitzer Prize winning book, focused public attention on the issue of eviction. As a result, scholars have begun to investigate and challenge some of the assumptions made in the book. Primarily, is eviction the cause of poverty or one of its consequences? This article explores several options in an attempt to explain the high number of evictions in America. These include, among others, the lack of affordable housing, failed governmental policies, the rise of institutional landlords and the role of courts. The article highlights some interventions that have begun to show progress in easing the burden of eviction. In the end, however, the paper concludes that the solution lies in a re-thinking of the government’s role in housing. Our laws and court processes must be reformed to acknowledge the fundamental right of housing. Until our legal system considers the rights of tenants as at least equivalent to the rights of landlords, we will continue to see these staggering eviction numbers