Bio

Bio


I work to understand how thermogenesis in adipose tissue is altered by changes in diet and metabolic health. In the long term I aim to find ways to specifically exploit thermogenic mechanisms to better treat diseases such as obesity, diabetes, cardiovascular disease and anorexia.

I am currently identifying and characterizing the neuronal circuits that respond to metabolic and dietary changes to elicit more or less thermogenesis. At the same time I examine the impact of these changes on the metabolic health of cells, tissues and whole organisms. To achieve this I combine the latest nueuromodulatory techniques such as opto- and chemogenetics with my extensive experience performing detailed in vivo and in vitro metabolic phenotyping.

Honors & Awards


  • Long-Term Fellowship, EMBO (10/01/13 - 09/30/15)
  • Equality Champion, Athena Swan (10/01/10 - 10/01/11)
  • Student Representative, Cambridge University Clinical School Graduate Education Committee (10/01/06 - 10/01/09)
  • Traveling Fellowship, Disease Models and Mechanisms (08/14/09)
  • Traveling Fellowship, EMBO (04/12/08)

Boards, Advisory Committees, Professional Organizations


  • Member, American Heart Association (2015 - Present)

Professional Education


  • Bachelor of Science, University of Manchester (2006)
  • Doctor of Philosophy, University of Cambridge (2011)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


I use optogenetic and chemogenetic techniques to modulate the activity of specific neuronal populations using a candidate-based approach. I couple these manipulations with behavioral and metabolic phenotyping to identify neuronal populations that elicit changes in brown adipose tissue thermogenic activity, basal metabolic rate, lipid and glucose homeostasis and/or arousal state. I then examine circuit connectivity using viral tracing techniques. I am always open to collaborations

Publications

All Publications


  • FGF21 Conducts a Metabolic Orchestra and Fat Is a Key Player. Endocrinology Whittle, A. J. 2016; 157 (5): 1722-4

    View details for DOI 10.1210/en.2016-1193

    View details for PubMedID 27149039

  • Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans NATURE COMMUNICATIONS Whittle, A. J., Jiang, M., Peirce, V., Relat, J., Virtue, S., Ebinuma, H., Fukamachi, I., Yamaguchi, T., Takahashi, M., Murano, T., Tatsuno, I., Takeuchi, M., Nakaseko, C., Jin, W., Jin, Z., Campbell, M., Schneider, W. J., Vidal-Puig, A., Bujo, H. 2015; 6

    Abstract

    Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFβ signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity.

    View details for DOI 10.1038/ncomms9951

    View details for Web of Science ID 000366380500004

    View details for PubMedID 26584636

  • Light and chemical control of neuronal circuits: possible applications in neurotherapy EXPERT REVIEW OF NEUROTHERAPEUTICS Whittle, A. J., Walsh, J., de Lecea, L. 2014; 14 (9): 1007-1017

    Abstract

    Millions of people worldwide suffer from diseases that result from a failure of central pathways to regulate behavioral and physiological processes. Advances in genetics and pharmacology have already allowed us to appreciate that rather than this dysregulation being systemic throughout the brain, it is usually rooted in specific subsets of dysfunctional cells within discrete neurological circuits. This article discusses the advent of opto- and chemogenetic tools and how they are providing the means to dissect these circuits with a degree of temporal and spatial sensitivity not previously possible. We also highlight the potential applications for treating disease and the key developments likely to have the greatest impact over the next 5 years.

    View details for DOI 10.1586/14737175.2014.948850

    View details for Web of Science ID 000341182900004

  • Pharmacological strategies for targeting BAT thermogenesis TRENDS IN PHARMACOLOGICAL SCIENCES Whittle, A., Relat-Pardo, J., Vidal-Puig, A. 2013; 34 (6): 347-355

    Abstract

    Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective. This review outlines the nature of these regulatory mechanisms both in terms of their cellular specificity and probable effectiveness given the physiological paradigms in which thermogenesis is activated. Similarly, their potential for being targeted by new or existing drugs is discussed, drawing on the known mechanisms of action of various pharmacological agents and some probable limitations that should be considered.

    View details for DOI 10.1016/j.tips.2013.04.004

    View details for Web of Science ID 000321094200008

    View details for PubMedID 23648356

  • BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions CELL Whittle, A. J., Carobbio, S., Martins, L., Slawik, M., Hondares, E., Jesus Vazquez, M., Morgan, D., Csikasz, R. I., Gallego, R., Rodriguez-Cuenca, S., Dale, M., Virtue, S., Villarroya, F., Cannon, B., Rahmouni, K., Lopez, M., Vidal-Puig, A. 2012; 149 (4): 871-885

    Abstract

    Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

    View details for DOI 10.1016/j.cell.2012.02.066

    View details for Web of Science ID 000303934700019

    View details for PubMedID 22579288

  • Nicotine Induces Negative Energy Balance Through Hypothalamic AMP-Activated Protein Kinase DIABETES Martinez de Morentin, P. B., Whittle, A. J., Ferno, J., Nogueiras, R., Dieguez, C., Vidal-Puig, A., Lopez, M. 2012; 61 (4): 807-817

    Abstract

    Smokers around the world commonly report increased body weight after smoking cessation as a major factor that interferes with their attempts to quit. Numerous controlled studies in both humans and rodents have reported that nicotine exerts a marked anorectic action. The effects of nicotine on energy homeostasis have been mostly pinpointed in the central nervous system, but the molecular mechanisms controlling its action are still not fully understood. The aim of this study was to investigate the effect of nicotine on hypothalamic AMP-activated protein kinase (AMPK) and its effect on energy balance. Here we demonstrate that nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK, decreased orexigenic signaling in the hypothalamus, increased energy expenditure as a result of increased locomotor activity, increased thermogenesis in brown adipose tissue (BAT), and alterations in fuel substrate utilization. Conversely, nicotine withdrawal or genetic activation of hypothalamic AMPK in the ventromedial nucleus of the hypothalamus reversed nicotine-induced negative energy balance. Overall these data demonstrate that the effects of nicotine on energy balance involve specific modulation of the hypothalamic AMPK-BAT axis. These targets may be relevant for the development of new therapies for human obesity.

    View details for DOI 10.2337/db11-1079

    View details for Web of Science ID 000301959800009

    View details for PubMedID 22315316

  • Using brown adipose tissue to treat obesity - the central issue TRENDS IN MOLECULAR MEDICINE Whittle, A. J., Lopez, M., Vidal-Puig, A. 2011; 17 (8): 405-411

    Abstract

    Current therapeutic strategies are proving inadequate to deal with growing obesity rates because of the inherent resistance of the human body to weight loss. The activation of human brown adipose tissue (BAT) represents an opportunity to increase energy expenditure and weight loss alongside improved lipid and glucose homeostasis. Research into the regulation of BAT has made increasing the thermogenic capacity of an individual to treat metabolic disease a plausible strategy, despite thermogenesis being under tight central nervous system control. Previous therapies targeted at the sympathetic nervous system have had deleterious effects because of a lack of organ specificity, but advances in our understanding of central BAT regulatory systems might open up better strategies to specifically stimulate BAT in obese individuals to aid weight reduction.

    View details for DOI 10.1016/j.molmed.2011.04.001

    View details for Web of Science ID 000294578400001

    View details for PubMedID 21602104

  • Pathogenic Lrrk2 substitutions and amyotrophic lateral sclerosis JOURNAL OF NEURAL TRANSMISSION Whittle, A. J., Ross, O. A., Naini, A., Gordon, P., Mistumoto, H., Dachsel, J. C., Stone, J. T., Wszolek, Z. K., Farrer, M. J., Przedborski, S. 2007; 114 (3): 327-329

    Abstract

    Pathogenic Lrrk2 Y1699C substitution observed in a large German-Canadian kindred presents a neurodegenerative disorder that is reminiscent of amyotrophic lateral sclerosis and Parkinsonism-Dementia Complex. We screened 54 patients with ALS for seven known Lrrk2 pathogenic substitutions in the Roc, COR and kinase domains. No mutations were observed suggesting that this locus does not have a major influence on the ALS phenotype. However we can not rule out other genetic variation at the LRRK2 locus may play a role in parkinsonian disorders with amyotrophic lateral sclerosis and may be considered candidates for genetic screening.

    View details for DOI 10.1007/s00702-006-0525-3

    View details for Web of Science ID 000244485200004

    View details for PubMedID 16865326

  • Genomewide association, Parkinson disease, and PARK10 AMERICAN JOURNAL OF HUMAN GENETICS Farrer, M. J., Haugarvoll, K., Ross, O. A., Stone, J. T., Whittle, A. J., Lincoln, S. J., Hulihan, M. M., Heckman, M. G., White, L. R., Aasly, J. O., Gibson, J. M., Gosal, D., Lynch, T., Wszolek, Z. K., Uitti, R. J., Toft, M. 2006; 78 (6): 1084-1088

    View details for Web of Science ID 000237553800020

    View details for PubMedID 16685661